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# Transplantation of Olfactory Ensheathing Cells: Properties and Therapeutic Effects after Transplantation into the Lesioned Nervous System

Quentin Delarue, Nicolas Guérout

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Quentin Delarue, Nicolas Guérout. Transplantation of Olfactory Ensheathing Cells: Properties and Therapeutic Effects after Transplantation into the Lesioned Nervous System. Neuroglia, 2022, 3 (1), pp.1-22. 10.3390/neuroglia3010001. hal-03707860

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Review

# Transplantation of Olfactory Ensheathing Cells: Properties and Therapeutic Effects after Transplantation into the Lesioned Nervous System

Quentin Delarue <fnref n="1" />,<fnref n="2" />,* and Nicolas Guérout <fnref n="1" />,<fnref n="2" />,* |

**Abstract:** The primary olfactory system (POS) is in permanent renewal, especially the primary olfactory neurons (PON) are renewed with a turnover of around four weeks, even in adulthood. The re-growth of these axons is helped by a specific population of glial cells: the olfactory ensheathing cells (OECs). In the POS, OECs constitute an "open-channel" in which the axons of PON cause regrowth from peripheral nervous system (PNS) to central nervous system (CNS). The remarkable role played by OECs into the POS has led scientists to investigate their properties and potential beneficial effects after transplantation in different lesion models of the CNS and PNS. In this review, we will resume and discuss more than thirty years of research regarding OEC studies. Indeed, after discussing the embryonic origins of OECs, we will describe the in vitro and in vivo properties exert at physiological state by these cells. Thereafter, we will present and talk over the effects of the transplantation of OECs after spinal cord injury, peripheral injury and other CNS injury models such as demyelinating diseases or traumatic brain injury. Finally, the mechanisms exerted by OECs in these different CNS and PNS lesion paradigms will be stated and we will conclude by presenting the innovations and future directions which can be considered to improve OECs properties and allow us to envisage their use in the near future in clinical applications.

**Keywords:** spinal cord injury; peripheral nerve injury; olfactory ensheathing cells; transplantation

<figure><img src="image_2.png" /></figure>

check for
updates

**Citation:** Delarue, Q.; Guérout, N. Transplantation of Olfactory Ensheathing Cells: Properties and Therapeutic Effects after Transplantation into the Lesioned Nervous System. *Neuroglia* **2022**, *3*, 1–22. https://doi.org/10.3390/neuroglia3010001

Academic Editors: James St John and Mo Chen

Received: 31 December 2021

Accepted: 25 January 2022

Published: 28 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

<figure><img src="image_3.png" /></figure>

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

## 1. Organization of the Olfactory System

The olfactory system is a tissue in which permanent regeneration occurs even in adulthood [1]. Indeed, the primary olfactory system (POS) is exposed to the external environment and to potential attacks such as pollution or viruses [2]. Moreover, for many animal species including mammals, olfaction is crucial to interact with their environment and their congeners. That is why the olfactory system and particularly the POS possesses intrinsic regeneration abilities. The main role of the POS is assured by the presence of primary olfactory neurons (PON). PON are bipolar neuronal cells that connect the peripheral nervous system (PNS) to the central nervous system (CNS). In effect, in the olfactory epithelium (OE) in the PNS, odorant molecules attach themselves to the PON which project the olfactory information to the olfactory bulbs (OB) into the CNS. Due to their exposition to toxics, PON are periodically renewed throughout life in mammals with a turnover of around four weeks. To do so, there is a persistent population of stem cells into the OE, the basal cells, which can give rise to the PON [3,4]. In the OE, there are also fibroblast-like supporting cells. These cells constitute the conjunctive tissue of the neuroepithelium and also play an active role in detoxification [5]. As mentioned above, PON are renewed every month by the basal cells, this process is very well orchestrated. Indeed, PON are selective of specific odorant molecules. Thus, these neurons constitute several families of cells grouped according to their expression of common olfactory receptors. These neurons are randomly arranged into the OE but project specifically to their

<footnote n="1">¹ EA3830 GRHV, Institute for Research and Innovation in Biomedicine (IRIB), Normandie University, UNIROUEN, 76000 Rouen, France</footnote>

<footnote n="2">² Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France</footnote>

<footnote>* Correspondence: quentin.delarue@univ-rouen.fr (Q.D.); nicolas.guerout@univ-rouen.fr (N.G.)</footnote>
<figure><img src="image_3.png" /></figure>

Review

# Transplantation of Olfactory Ensheathing Cells: Properties and Therapeutic Effects after Transplantation into the Lesioned Nervous System

Quentin Delarue <fnref n="1" />,<fnref n="2" />,* and Nicolas Guérout <fnref n="1" />,<fnref n="2" />,* |

**Abstract:** The primary olfactory system (POS) is in permanent renewal, especially the primary olfactory neurons (PON) are renewed with a turnover of around four weeks, even in adulthood. The re-growth of these axons is helped by a specific population of glial cells: the olfactory ensheathing cells (OECs). In the POS, OECs constitute an "open-channel" in which the axons of PON cause regrowth from peripheral nervous system (PNS) to central nervous system (CNS). The remarkable role played by OECs into the POS has led scientists to investigate their properties and potential beneficial effects after transplantation in different lesion models of the CNS and PNS. In this review, we will resume and discuss more than thirty years of research regarding OEC studies. Indeed, after discussing the embryonic origins of OECs, we will describe the in vitro and in vivo properties exert at physiological state by these cells. Thereafter, we will present and talk over the effects of the transplantation of OECs after spinal cord injury, peripheral injury and other CNS injury models such as demyelinating diseases or traumatic brain injury. Finally, the mechanisms exerted by OECs in these different CNS and PNS lesion paradigms will be stated and we will conclude by presenting the innovations and future directions which can be considered to improve OECs properties and allow us to envisage their use in the near future in clinical applications.

**Keywords:** spinal cord injury; peripheral nerve injury; olfactory ensheathing cells; transplantation

<figure><img src="image_4.png" /></figure>

check for
updates

**Citation:** Delarue, Q.; Guérout, N. Transplantation of Olfactory Ensheathing Cells: Properties and Therapeutic Effects after Transplantation into the Lesioned Nervous System. *Neuroglia* **2022**, *3*, 1–22. https://doi.org/10.3390/neuroglia3010001

Academic Editors: James St John and Mo Chen

Received: 31 December 2021

Accepted: 25 January 2022

Published: 28 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

<figure><img src="image_5.png" /></figure>

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

## 1. Organization of the Olfactory System

The olfactory system is a tissue in which permanent regeneration occurs even in adulthood [1]. Indeed, the primary olfactory system (POS) is exposed to the external environment and to potential attacks such as pollution or viruses [2]. Moreover, for many animal species including mammals, olfaction is crucial to interact with their environment and their congeners. That is why the olfactory system and particularly the POS possesses intrinsic regeneration abilities. The main role of the POS is assured by the presence of primary olfactory neurons (PON). PON are bipolar neuronal cells that connect the peripheral nervous system (PNS) to the central nervous system (CNS). In effect, in the olfactory epithelium (OE) in the PNS, odorant molecules attach themselves to the PON which project the olfactory information to the olfactory bulbs (OB) into the CNS. Due to their exposition to toxics, PON are periodically renewed throughout life in mammals with a turnover of around four weeks. To do so, there is a persistent population of stem cells into the OE, the basal cells, which can give rise to the PON [3,4]. In the OE, there are also fibroblast-like supporting cells. These cells constitute the conjunctive tissue of the neuroepithelium and also play an active role in detoxification [5]. As mentioned above, PON are renewed every month by the basal cells, this process is very well orchestrated. Indeed, PON are selective of specific odorant molecules. Thus, these neurons constitute several families of cells grouped according to their expression of common olfactory receptors. These neurons are randomly arranged into the OE but project specifically to their

<footnote n="1">¹ EA3830 GRHV, Institute for Research and Innovation in Biomedicine (IRIB), Normandie University, UNIROUEN, 76000 Rouen, France</footnote>

<footnote n="2">² Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen, France</footnote>

<footnote>* Correspondence: quentin.delarue@univ-rouen.fr (Q.D.); nicolas.guerout@univ-rouen.fr (N.G.)</footnote>
targets into the OB [6,7]. The renewal of PON and their targeted axonal regrowth is facilitated
by the presence of a specific population of glial cells. In fact, in the OE and the outer nerve
layer (ONL) of the OB, are located the olfactory ensheathing cells (OECs) [8]. These cells in
the POS exert the same function as the non-myelinating Schwann cells (SCs) in the PNS, they
ensheathe the axons without forming myelin in order to protect and guide them. In contrast
to the SCs, OECs allow the regrowth of axons in the PNS (OE) but also in the CNS (OB).
The common properties shared by OECs and SCs have sometimes led scientists to describe
them as olfactory Schwann cells [9]. In 1990, Doucette called them "ensheathing cells" for
the first time [8]. The renewal of OECs at the adult stage in physiological conditions is not
well described. It is thought that these cells do not proliferate in adulthood [10]. Their main
role would be to constitute an "open-channel" in which the axons of PON could regrowth
specifically from PNS to CNS [11].

2. Origin and Cellular Heterogeneity of the OECs

Until 2010/2011, it was thought that the embryonic origin of the OECs was the olfactory placode. However, in 2010 and 2011, two studies, based on fate mapping experiments, demonstrated that OECs such as SCs are derived from the neural crest [12,13]. This common origin shared by SCs and OECs explains the fact that these cells express mainly the same markers and play a similar role in their specific nervous system compartment [14]. Indeed, in vitro, OECs and SCs cultures are characterized by their expression of GFAP and P75NTR [14]. The common origin of these two populations of cells does not mean that OECs and SCs are identical. Indeed, in vivo the POS OECs do not produce myelin, they ensheath PON axons in bundles and not individually as would SCs. Moreover, OECs can migrate from the PNS to the CNS and thereby can intermingle with astrocytes. On the opposite, SCs cannot mix with astrocytes and cannot migrate into the CNS [15]. These different interactions with astrocytes can be explain by the fact that OECs and SCs express differentially extracellular matrix (ECM) genes as demonstrated by transcriptomic studies [16,17].

In the same way, OECs are not constituted by a uniform population of cells. Indeed,
as described above, OECs ensheathe PONs and can be found in the PNS, in the OE, or in
the CNS, in the ONL of the OB. Several studies have reported that, according to their origin,
OM or OB, OECs express distinct properties in vitro [18,19]. Thereafter, based on microarray
analyses, we have demonstrated that OECs from OM and OECs from OB, respectively OM-
OECs and OB-OECs, display distinct gene expression patterns. In effect, OM-OECs express
preferentially genes involved in the regulation of the ECM such as MMP2, TIMP2, ADAMTS-
4 or thrombospondin 1 and 2, whereas OB-OECs express preferentially genes involved in
"nervous system development" processes such as BDNF, Reelin or MBP [20]. Based on bulk
RNA seq experiments, these results have been expanded and confirmed recently [21].

Furthermore, in vitro and in vivo studies have demonstrated that OB-OECs are in fact composed of two different subpopulations of cells [22–24]. Indeed, Windus et al. demonstrated elegantly that OB-OECs constitute a heterogeneous population of cells [25]. Then, a transcriptomic study confirmed that two subpopulations of OECs, characterized by their differential expression of P75NTR, named P75High and P75Low, are present in cultures obtained from OB [26]. Gene expression profiling analysis of these cells allows proposing a specific role during PON renewal. P75High cells are involved in fasciculation and defasciculation of the axons of the PON and P75Low cells in axonal guidance [26].

As described above, P75NTR is used as the main marker of OECs. Although this marker
is used to characterize OECs in vitro and in vivo, several studies have tried to find additional
markers allowing researchers to differentiate OECs from SCs and to define specifically the
sub-populations of OECs. The first studies investigating markers expressed by OECs used
markers already known as being expressed by astrocytes or SCs [27,28]. Indeed, OECs,
until the beginning of the 1990s, were defined as olfactory nerve SCs or olfactory nerve
glia cells. Based on these investigations, it was demonstrated that OECs express GFAP,
S100β and P75NTR [27,28]. These markers were found to be expressed both in vitro and
in vivo [24,29–33]. Then, additional markers were found to be potentially expressed in vivo by
targets into the OB [6,7]. The renewal of PON and their targeted axonal regrowth is facilitated by the presence of a specific population of glial cells. In fact, in the OE and the outer nerve layer (ONL) of the OB, are located the olfactory ensheathing cells (OECs) [8]. These cells in the POS exert the same function as the non-myelinating Schwann cells (SCs) in the PNS, they ensheathe the axons without forming myelin in order to protect and guide them. In contrast to the SCs, OECs allow the regrowth of axons in the PNS (OE) but also in the CNS (OB). The common properties shared by OECs and SCs have sometimes led scientists to describe them as olfactory Schwann cells [9]. In 1990, Doucette called them "ensheathing cells" for the first time [8]. The renewal of OECs at the adult stage in physiological conditions is not well described. It is thought that these cells do not proliferate in adulthood [10]. Their main role would be to constitute an "open-channel" in which the axons of PON could regrowth specifically from PNS to CNS [11].

## 2. Origin and Cellular Heterogeneity of the OECs

Until 2010/2011, it was thought that the embryonic origin of the OECs was the olfactory placode. However, in 2010 and 2011, two studies, based on fate mapping experiments, demonstrated that OECs such as SCs are derived from the neural crest [12,13]. This common origin shared by SCs and OECs explains the fact that these cells express mainly the same markers and play a similar role in their specific nervous system compartment [14]. Indeed, in vitro, OECs and SCs cultures are characterized by their expression of GFAP and P75NTR [14]. The common origin of these two populations of cells does not mean that OECs and SCs are identical. Indeed, in vivo the POS OECs do not produce myelin, they ensheath PON axons in bundles and not individually as would SCs. Moreover, OECs can migrate from the PNS to the CNS and thereby can intermingle with astrocytes. On the opposite, SCs cannot mix with astrocytes and cannot migrate into the CNS [15]. These different interactions with astrocytes can be explained by the fact that OECs and SCs express differentially extracellular matrix (ECM) genes as demonstrated by transcriptomic studies [16,17].

In the same way, OECs are not constituted by a uniform population of cells. Indeed, as described above, OECs ensheath PONs and can be found in the PNS, in the OE, or in the CNS, in the ONL of the OB. Several studies have reported that, according to their origin, OM or OB, OECs express distinct properties in vitro [18,19]. Thereafter, based on microarray analyses, we have demonstrated that OECs from OM and OECs from OB, respectively OM-OECs and OB-OECs, display distinct gene expression patterns. In effect, OM-OECs express preferentially genes involved in the regulation of the ECM such as MMP2, TIMP2, ADAMTS-4 or thrombospondin 1 and 2, whereas OB-OECs express preferentially genes involved in "nervous system development" processes such as BDNF, Reelin or MBP [20]. Based on bulk RNA seq experiments, these results have been expanded and confirmed recently [21].

Furthermore, in vitro and in vivo studies have demonstrated that OB-OECs are in fact composed of two different subpopulations of cells [22–24]. Indeed, Windus et al. demonstrated elegantly that OB-OECs constitute a heterogeneous population of cells [25]. Then, a transcriptomic study confirmed that two subpopulations of OECs, characterized by their differential expression of P75NTR, named P75High and P75Low, are present in cultures obtained from OB [26]. Gene expression profiling analysis of these cells allows proposing a specific role during PON renewal. P75High cells are involved in fasciculation and defasciculation of the axons of the PON and P75Low cells in axonal guidance [26].

As described above, P75NTR is used as the main marker of OECs. Although this marker is used to characterize OECs in vitro and in vivo, several studies have tried to find additional markers allowing researchers to differentiate OECs from SCs and to define specifically the sub-populations of OECs. The first studies investigating markers expressed by OECs used markers already known as being expressed by astrocytes or SCs [27,28]. Indeed, OECs, until the beginning of the 1990s, were defined as olfactory nerve SCs or olfactory nerve glia cells. Based on these investigations, it was demonstrated that OECs express GFAP, S100β and P75NTR [27,28]. These markers were found to be expressed both in vitro and in vivo [24,29–33]. Then, additional markers were found to be potentially expressed in vivo by
OECs such as O4, Neuropeptide Y (NPY) or TROY [34–37]. Another marker which is currently used also to define OECs is E-NCAM. The expression of E-NCAM by OECs was reported for the first time in 1996 by Franceschini and Barnett [38]. In this study they demonstrate that E-NCAM is expressed in vitro and in vivo. These studies have mainly investigated the expression of markers of OECs into the OB in vivo or from cultures of OECs obtained from OB in vitro.

In 2003, Au and Roskams characterized the expression of markers of OECs from OM in vivo and in vitro [39]. They showed that OM-OECs express also P75, S100β, GFAP and O4 both in vitro and in vivo. They demonstrated also that OM-OECs express specific markers such as vimentin, nestin, or NG2 in vitro and CD44 or PACAP both in vitro and in vivo [39]. Interestingly, OECs expression markers’ characterization has been also investigated in fish. In effect, several studies have demonstrated that OECs in different fish species such as zebrafish express mainly the same markers they do in rodents [40,41].

It is important to summarize and differentiate the markers expressed by OECs in vitro and those expressed in vivo. Indeed, due to differences in experimental paradigms, such as the age of animals used to characterize expression markers; notably, in vivo expression of several markers has been investigated during development in newborn rats. Due to the difficulty of separating the markers expressed, especially by OECs and those by the closely associated cells, to date there is still no consensus regarding the specific and differential expression of OM and OB OECs. However, based on different reviews and meta-analysis, we can summarize that:

In culture, OM and OB OECs express P75NTR, GFAP and E-NCAM [42,43], and in vivo, OM and OB OECs express P75NTR, GFAP, E-NCAM, S100β, vimentin and NPY [42,43] (Figure 1b).

<figure><img src="image_4.png" /><figcaption>**Figure 1.** Culture, characterization and main therapeutic application of olfactory ensheathing cells. (a) OM primary cultures generate 10% of OECs while OB primary cultures generate 50% of OECs. (b) OECs are identified in vivo by the expression of p75NTR, GFAP, E-NCAM, S100b, vimentin and NPY, and in vitro by p75NTR, GFAP and E-NCAM. (c) The main therapeutic effects of OECs are linked to secretion of neurotrophic factors (NGF, BDNF, GDNF or CNTF), and by the secretion of molecules modulating the extracellular matrix (laminin, fibronectin, type IV collagen, MMP2 or SPARC). (d) The main pathological models showing beneficial effects of the transplantation of OECs. Blue rectangle concerns brain injury models, green rectangle concerns peripheral nerve injury models and red rectangle concerns spinal cord injury models. NGF: Nerve Growth Factor, BDNF: Brain Derived Neurotrophic Factor, GDNF: Glial Derived Neurotrophic Factor, CNTF: Ciliary Neurotrophic Factor.</figcaption></figure>
OECs such as O4, Neuropeptide Y (NPY) or TROY [34–37]. Another marker which is currently used also to define OECs is E-NCAM. The expression of E-NCAM by OECs was reported for the first time in 1996 by Franceschini and Barnett [38]. In this study they demonstrate that E-NCAM is expressed in vitro and in vivo. These studies have mainly investigated the expression of markers of OECs into the OB in vivo or from cultures of OECs obtained from OB in vitro.

In 2003, Au and Roskams characterized the expression of markers of OECs from OM in vivo and in vitro [39]. They showed that OM-OECs express also P75, S100β, GFAP and O4 both in vitro and in vivo. They demonstrated also that OM-OECs express specific markers such as vimentin, nestin, or NG2 in vitro and CD44 or PACAP both in vitro and in vivo [39]. Interestingly, OECs expression markers’ characterization has been also investigated in fish. In effect, several studies have demonstrated that OECs in different fish species such as zebrafish express mainly the same markers they do in rodents [40,41].

It is important to summarize and differentiate the markers expressed by OECs in vitro and those expressed in vivo. Indeed, due to differences in experimental paradigms, such as the age of animals used to characterize expression markers; notably, in vivo expression of several markers has been investigated during development in newborn rats. Due to the difficulty of separating the markers expressed, especially by OECs and those by the closely associated cells, to date there is still no consensus regarding the specific and differential expression of OM and OB OECs. However, based on different reviews and meta-analysis, we can summarize that:

In culture, OM and OB OECs express P75NTR, GFAP and E-NCAM [42,43], and in vivo, OM and OB OECs express P75NTR, GFAP, E-NCAM, S100β, vimentin and NPY [42,43] (Figure 1b).

<figure><img src="image_6.png" /><figcaption>**Figure 1.** Culture, characterization and main therapeutic application of olfactory ensheathing cells. (a) OM primary cultures generate 10% of OECs while OB primary cultures generate 50% of OECs. (b) OECs are identified in vivo by the expression of p75NTR, GFAP, E-NCAM, S100b, vimentin and NPY, and in vitro by p75NTR, GFAP and E-NCAM. (c) The main therapeutic effects of OECs are linked to secretion of neurotrophic factors (NGF, BDNF, GDNF or CNTF), and by the secretion of molecules modulating the extracellular matrix (laminin, fibronectin, type IV collagen, MMP2 or SPARC). (d) The main pathological models showing beneficial effects of the transplantation of OECs. Blue rectangle concerns brain injury models, green rectangle concerns peripheral nerve injury models and red rectangle concerns spinal cord injury models. NGF: Nerve Growth Factor, BDNF: Brain Derived Neurotrophic Factor, GDNF: Glial Derived Neurotrophic Factor, CNTF: Ciliary Neurotrophic Factor.</figcaption></figure>
That is why, due to the absence of consensual specific biomarkers, it is still difficult to
differentiate SCs and OECs.

3. OECs Properties

Even if OECs are constituted by several sub-populations, all these cells share common expression of specific markers. Moreover, independently of their origin, we can give an overview of the properties of the OECs. It is important to note that we made a choice to develop deeply the properties of OECs regarding phagocytosis and modulation of inflammation processes. Indeed, the secreting and myelinating properties of OECs have been already the subject of several reviews, whereas the immunomodulatory competencies of OECs have been reported more recently.

The studies investigating the properties of the OECs have been mainly conducted in vitro. In 1992, Ramon-Cueto and Nieto-Sampedro described the primary cultures of OECs obtained from OB [44]. They described that these cultures are composed of a mixture of P75 positive cells and fibronectin positive cells. Since then, P75 has been used as a pan-marker to characterize and quantify the OECs in culture. Mostly, the different studies characterizing the OECs report that the ratio between OECs, P75 positive cells, and fibroblasts/stromal cells, fibronectin positive cells, is around 50/50 in primary OB cultures (Figure 1a). Then, several purification techniques have been described allowing to obtain more than 90% of OECs [45–47]. The first descriptions of the cultures of OECs obtained from OM have been reported later [48,49]. It is important to note that in primary cultures the ratio of OECs/fibroblasts is very low. Indeed, the authors mainly report that the proportion of OECs in primary OM cultures is around 10% (Figure 1a). In the same way, several purification technics have been described in order to obtain highly purified cultures of OECs [50]. Based on these different culture models, several studies have reported that OECs secrete a wide range of trophic factors and ECM proteins (Figure 1c). Indeed, it has been demonstrated that OECs express trophic factors such as NGF, BDNF, GDNF or CNTF and ECM molecules or ECM modulating molecules such as: laminin, fibronectin, type 4 collagen, MMP2 or SPARC [51–57] (Figure 1c).

These properties have prompted researchers to investigate the effects of OECs in co-culture with different neural cell lines [58–62]. It appears that OECs enhance axonal and neurite outgrowth, increase survival and differentiation of neural stem cells (NSC) [63]. More interestingly, several studies have described that these positive effects can be induced by conditioned medium obtained from OECs primary cultures [58,60,64].

Myelinating properties of OECs have been also investigated in vitro. Indeed, in vivo in physiological conditions, OECs do not form myelin around the PON. However, it has been hypothesized that this was maybe due to the small size of the PON axons. The myelinating properties of the OECs are still under debate. In effect, some publications described that OECs in vitro ensheathe bundles of axons without forming myelin [65]. Other studies described that OECs form myelin in vitro [63]. Interestingly, in these publications, the authors described that OECs form a “Schwann cell-like” myelin with the expression of the peripheric myelin protein P0.

Another very important aspect which has been widely investigated, is the behavior of
OECs with astrocytes and fibroblasts [15,66]. Indeed, in order to mimic the scar present
after injury, authors performed co-cultures of OECs with these two cell types. The different
studies report that OECs can intermingle with astrocytes and fibroblasts without inducing
the hypertrophy of these cells. This behavior constitutes one of the main differences
between OECs and SCs. In contrast, SCs do not mix themselves with astrocytes and
fibroblasts. Moreover, co-culture of astrocytes and SCs induces astrocyte hypertrophy.

More recently, new properties of OECs have been investigated and reported. Ad-
ditional to the previous characteristics, OECs possess immunomodulatory competences.
Indeed, due to important PON renewal and proximity to the periphery, inflammation in
the OB and phagocytosis are substantial in the physiologic state [67].
That is why, due to the absence of consensual specific biomarkers, it is still difficult to
differentiate SCs and OECs.

3. OECs Properties

Even if OECs are constituted by several sub-populations, all these cells share common expression of specific markers. Moreover, independently of their origin, we can give an overview of the properties of the OECs. It is important to note that we made a choice to develop deeply the properties of OECs regarding phagocytosis and modulation of inflammation processes. Indeed, the secreting and myelinating properties of OECs have been already the subject of several reviews, whereas the immunomodulatory competencies of OECs have been reported more recently.

The studies investigating the properties of the OECs have been mainly conducted in vitro. In 1992, Ramon-Cueto and Nieto-Sampedro described the primary cultures of OECs obtained from OB [44]. They described that these cultures are composed of a mixture of P75 positive cells and fibronectin positive cells. Since then, P75 has been used as a pan-marker to characterize and quantify the OECs in culture. Mostly, the different studies characterizing the OECs report that the ratio between OECs, P75 positive cells, and fibroblasts/stromal cells, fibronectin positive cells, is around 50/50 in primary OB cultures (Figure 1a). Then, several purification techniques have been described allowing to obtain more than 90% of OECs [45–47]. The first descriptions of the cultures of OECs obtained from OM have been reported later [48,49]. It is important to note that in primary cultures the ratio of OECs/fibroblasts is very low. Indeed, the authors mainly report that the proportion of OECs in primary OM cultures is around 10% (Figure 1a). In the same way, several purification technics have been described in order to obtain highly purified cultures of OECs [50]. Based on these different culture models, several studies have reported that OECs secrete a wide range of trophic factors and ECM proteins (Figure 1c). Indeed, it has been demonstrated that OECs express trophic factors such as NGF, BDNF, GDNF or CNTF and ECM molecules or ECM modulating molecules such as: laminin, fibronectin, type 4 collagen, MMP2 or SPARC [51–57] (Figure 1c).

These properties have prompted researchers to investigate the effects of OECs in co-culture with different neural cell lines [58-62]. It appears that OECs enhance axonal and neurite outgrowth, increase survival and differentiation of neural stem cells (NSC) [63]. More interestingly, several studies have described that these positive effects can be induced by conditioned medium obtained from OECs primary cultures [58,60,64].

Myelinating properties of OECs have been also investigated in vitro. Indeed, in vivo in physiological conditions, OECs do not form myelin around the PON. However, it has been hypothesized that this was maybe due to the small size of the PON axons. The myelinating properties of the OECs are still under debate. In effect, some publications described that OECs in vitro ensheathe bundles of axons without forming myelin [65]. Other studies described that OECs form myelin in vitro [63]. Interestingly, in these publications, the authors described that OECs form a “Schwann cell-like” myelin with the expression of the peripheric myelin protein P0.

Another very important aspect which has been widely investigated, is the behavior of
OECs with astrocytes and fibroblasts [15,66]. Indeed, in order to mimic the scar present
after injury, authors performed co-cultures of OECs with these two cell types. The different
studies report that OECs can intermingle with astrocytes and fibroblasts without inducing
the hypertrophy of these cells. This behavior constitutes one of the main differences
between OECs and SCs. In contrast, SCs do not mix themselves with astrocytes and
fibroblasts. Moreover, co-culture of astrocytes and SCs induces astrocyte hypertrophy.

More recently, new properties of OECs have been investigated and reported. Ad-
ditional to the previous characteristics, OECs possess immunomodulatory competences.
Indeed, due to important PON renewal and proximity to the periphery, inflammation in
the OB and phagocytosis are substantial in the physiologic state [67].
During early development of the POS, PON apoptosis is induced following inappropri-
ate projections within their target [68,69]. In post-natal mice and in adult lifespan, PON re-
newal and apoptosis decrease compared to the embryonic stage but are still present [70,71].
Throughout the adult CNS, microglial cells are the main phagocytic and regulatory cells of
inflammatory balance. In contrast to the OBs, this role is additionally supported by OECs.
Especially, OECs produce macrophage migration inhibitory factor (MIF). MIF is a cytokine
which plays important roles in innate immune responses, inflammation, cell proliferation,
cell migration and apoptosis. Moreover, MIF limits microglial and macrophage migra-
tion to the OB [72–74]. Therefore, several in vitro and in vivo studies have investigated
phagocytic properties of OECs [11,75–81]. In these studies, phagocytic activity has been
identified as an important mechanism necessary to clear apoptotic and necrotic cells and
to initiate neuronal regrowth. Nazareth et al., have shown that OECs phagocytic activity
starts from E13.5 in mice, during the development of the olfactory system, and continues
throughout life. The phagocytic properties of OECs have been compared to other cells. It
appears, that OECs are more efficient than SCs but less efficient than microglial cells. The
authors explain that internalization and trafficking of endosomes and lysosomes are slower
than those of microglia [79]. Many phagocytic receptors were identified on OECs such
as the phosphatidyl serine receptor [75], MFG-E8 receptor [77], toll-like receptors 2 and
4 [75,82] and the mannose receptor [83]. These receptors give the possibility to phagocyte
neuronal debris, necrotic cells and bacteria. In adult OB, removal of neuronal debris by
phagocytosis is necessary for neuronal survival, their renewal and neurite outgrowth.
Indeed, cellular and axonal debris inhibit cellular proliferation and axonal regrowth and
increase inflammation processes, which in turn decrease neurogenesis. The inflammation
processes allow initiation of tissue regeneration in physiologic and pathologic contexts.
In other parts of the CNS, cytokines involved in inflammation processes are secreted by
microglial cells, astrocytes and immune cells, as described previously [84]. In the OBs,
OECs contribute to inflammatory modulation. In response to olfactory bacteria infiltration,
OECs detect lipopolysaccharide and produce tumor necrosis factors alpha (TNF-α), C-X-C
Motif Chemokine Ligand 1 and 2 (CXCL1, CXCL2) and IL1-RA [75,85,86]. Lankford et al.,
showed that TNF-α stimulates proliferation of OECs during chronic exposure and their
migration by binding to the TNF receptor 1 [87] as described for microglial cells [88]. In
sum, OECs have similar capacity to immune cells, making them the main cells regulating
inflammatory and regeneration processes in the OBs.

Altogether, the specific properties of the OECs have led scientists to investigate the
effects of OEC transplantation in different lesion models of the CNS and PNS.

4. A Brief History of the Use of the OECs for Repairing the Nervous System

The first studies reporting the effects of the transplantation of OECs in vivo were
published in the mid 1990s. Although effects of the transplantations of OECs have been
massively studied after spinal cord injury (SCI), the first studies investigated the effects
of these cells in other lesion paradigms. Indeed, the first study, in 1994, was based on a
rhizotomy lesion model. The thoracic dorsal root ganglion (DRG) was transected, and
purified OB-OECs were transplanted [29]. The authors reported that OB-OEC transplanta-
tion induced regeneration of the sensory axons. Then, a second model based on a lesion
of the brain, a fimbria-fornix transection, showed that transplantation of OB-OECs en-
hances growth of axons and that, in this model, OECs survive a minimum of 4 weeks after
transplantation [89]. In 1996, Franklin et al. studied the role of OB-OEC transplantation
in a demyelinating injury model of the ventral spinal cord based on X-ray irradiation and
ethidium bromide injection. In this model, they show for the first time that OECs can
produce peripheric P0 positive myelin [90]. Finally, in 1997 and 1998, SCI related models
were investigated. In 1997, Li et al. demonstrated that transplantation of OB-OECs after
corticospinal tract (CST) transection enhances axonal regrowth and functional recovery [91].
In 1998, Ramon-Cueto et al. demonstrated that after a complete transection of the spinal
During early development of the POS, PON apoptosis is induced following inappropri-
ate projections within their target [68,69]. In post-natal mice and in adult lifespan, PON re-
newal and apoptosis decrease compared to the embryonic stage but are still present [70,71].
Throughout the adult CNS, microglial cells are the main phagocytic and regulatory cells of
inflammatory balance. In contrast to the OBs, this role is additionally supported by OECs.
Especially, OECs produce macrophage migration inhibitory factor (MIF). MIF is a cytokine
which plays important roles in innate immune responses, inflammation, cell proliferation,
cell migration and apoptosis. Moreover, MIF limits microglial and macrophage migra-
tion to the OB [72–74]. Therefore, several in vitro and in vivo studies have investigated
phagocytic properties of OECs [11,75–81]. In these studies, phagocytic activity has been
identified as an important mechanism necessary to clear apoptotic and necrotic cells and
to initiate neuronal regrowth. Nazareth et al., have shown that OECs phagocytic activity
starts from E13.5 in mice, during the development of the olfactory system, and continues
throughout life. The phagocytic properties of OECs have been compared to other cells. It
appears, that OECs are more efficient than SCs but less efficient than microglial cells. The
authors explain that internalization and trafficking of endosomes and lysosomes are slower
than those of microglia [79]. Many phagocytic receptors were identified on OECs such
as the phosphatidyl serine receptor [75], MFG-E8 receptor [77], toll-like receptors 2 and
4 [75,82] and the mannose receptor [83]. These receptors give the possibility to phagocyte
neuronal debris, necrotic cells and bacteria. In adult OB, removal of neuronal debris by
phagocytosis is necessary for neuronal survival, their renewal and neurite outgrowth.
Indeed, cellular and axonal debris inhibit cellular proliferation and axonal regrowth and
increase inflammation processes, which in turn decrease neurogenesis. The inflammation
processes allow initiation of tissue regeneration in physiologic and pathologic contexts.
In other parts of the CNS, cytokines involved in inflammation processes are secreted by
microglial cells, astrocytes and immune cells, as described previously [84]. In the OBs,
OECs contribute to inflammatory modulation. In response to olfactory bacteria infiltration,
OECs detect lipopolysaccharide and produce tumor necrosis factors alpha (TNF-α), C-X-C
Motif Chemokine Ligand 1 and 2 (CXCL1, CXCL2) and IL1-RA [75,85,86]. Lankford et al.,
showed that TNF-α stimulates proliferation of OECs during chronic exposure and their
migration by binding to the TNF receptor 1 [87] as described for microglial cells [88]. In
sum, OECs have similar capacity to immune cells, making them the main cells regulating
inflammatory and regeneration processes in the OBs.

Altogether, the specific properties of the OECs have led scientists to investigate the
effects of OEC transplantation in different lesion models of the CNS and PNS.

4. A Brief History of the Use of the OECs for Repairing the Nervous System

The first studies reporting the effects of the transplantation of OECs in vivo were
published in the mid 1990s. Although effects of the transplantations of OECs have been
massively studied after spinal cord injury (SCI), the first studies investigated the effects
of these cells in other lesion paradigms. Indeed, the first study, in 1994, was based on a
rhizotomy lesion model. The thoracic dorsal root ganglion (DRG) was transected, and
purified OB-OECs were transplanted [29]. The authors reported that OB-OEC transplanta-
tion induced regeneration of the sensory axons. Then, a second model based on a lesion
of the brain, a fimbria-fornix transection, showed that transplantation of OB-OECs en-
hances growth of axons and that, in this model, OECs survive a minimum of 4 weeks after
transplantation [89]. In 1996, Franklin et al. studied the role of OB-OEC transplantation
in a demyelinating injury model of the ventral spinal cord based on X-ray irradiation and
ethidium bromide injection. In this model, they show for the first time that OECs can
produce peripheric P0 positive myelin [90]. Finally, in 1997 and 1998, SCI related models
were investigated. In 1997, Li et al. demonstrated that transplantation of OB-OECs after
corticospinal tract (CST) transection enhances axonal regrowth and functional recovery [91].
In 1998, Ramon-Cueto et al. demonstrated that after a complete transection of the spinal
cord, OB-OEC transplantation induces axonal regrowth. It is very important to note that all
these studies were performed in rat models and that OECs were obtained from OBs [92].

In 1999, Verdu et al. investigated for the first time the effects of OECs after a le-
sion of the PNS, sciatic nerve (SN) transection, and showed that OECs enhance axonal
regrowth [93].

In 2000, Kato et al. used for the first time OM-OECs for transplantation after SCI in rats. The cells were obtained from the olfactory nerve [94]. Moreover, in this study the OM-OECs were obtained from human. The same year, the same research team reported that OECs obtained from pigs OB can induce axonal regrowth after transplantation in injured rats [95].

In 2002, Lu et al. showed for the first time that a delayed transplantation of OM-OECs, 4 weeks after SCI, can induce axonal regrowth and functional recovery in rats [96].

The first study regarding the effects of OEC transplantation in a large animal was published in 2004. In fact, the authors transplanted OECs obtained from pigs, into the lesioned spinal cords of non-human primates. They showed also in this study that OEC transplantation enhances remyelination [97].

In 2004, the first study regarding the effects of OEC transplantation in context of de-
generative diseases was published. Indeed, Agrawal et al. published a study showing that
OEC transplantation can restore deficits induced in an experimental model of Parkinson's
disease [98].

Finally, in 2005, Féron et al. reported the first clinical study in human. In this phase
one clinical trial, autologous OEC transplantation was performed in patients suffering
SCI [99].

**5. Transplantation of OECs after Spinal Cord Injury**

Between one third and half of the publications related to OECs investigated the effects of their transplantation after SCI. Indeed, as mentioned above, since the second half of the nineties the unique properties of OECs have encouraged researchers to use these cells as therapy after various SCI models such as contusion, transection or demyelination. Therefore, the effects of OEC transplantation after SCI are well documented and the positive and negative effects can be discussed.

It is important to note that, even if DRGs are anatomically included in the PNS, a rhizotomy lesion model will be discussed in this section. The fact that axonal regrowth of the sensory axons into the spinal cord is one of the main outcomes of this lesion model, makes it, in our view, an SCI model.

In this section we will differentiate three lesion paradigms: (1) Lesions of the DRG or rhizotomy, as described above, this model should be considered a CNS lesion model, however, the injury site is in the PNS. (2) Traumatic SCI, lesion models regroup contusion and transection, these models are the most widely used SCI models. (3) Demyelinating SCI, in particular irradiation models, these models are mechanistically very informative however, properties and survival of OECs differ from the other SCI models.

Rhizotomy lesion model: this model is very interesting. As described above, it constitutes the first model in which beneficial effects of the transplantation of OECs was reported. Moreover, it appears that this model is the one in which OEC transplantations are least effective. Indeed, the ratio of studies describing beneficial effects and those describing the absence of effects is around 50%. In fact, the first reported studies describe positive effects after transplantation of OECs in the rhizotomy model [29,100]. In contrast, more recent studies report that OEC transplantation has no effect in this lesion model [101–103]. The main difference between these studies is the injection site. Indeed, in the two first studies the OECs were injected into the dorsal root entry zone (DREZ), at the frontier between the PNS and the CNS, whereas at the opposite in the three other studies OECs have been injected into the DRG, in the PNS. These contradictory results seem to indicate that OECs can promote axonal regrowth of the spinal sensory axons when they are injected into the spinal cord but that these cells cannot migrate from the PNS to the CNS through the
cord, OB-OEC transplantation induces axonal regrowth. It is very important to note that all
these studies were performed in rat models and that OECs were obtained from OBs [92].

In 1999, Verdu et al. investigated for the first time the effects of OECs after a le-
sion of the PNS, sciatic nerve (SN) transection, and showed that OECs enhance axonal
regrowth [93].

In 2000, Kato et al. used for the first time OM-OECs for transplantation after SCI in rats. The cells were obtained from the olfactory nerve [94]. Moreover, in this study the OM-OECs were obtained from human. The same year, the same research team reported that OECs obtained from pigs OB can induce axonal regrowth after transplantation in injured rats [95].

In 2002, Lu et al. showed for the first time that a delayed transplantation of OM-OECs, 4 weeks after SCI, can induce axonal regrowth and functional recovery in rats [96].

The first study regarding the effects of OEC transplantation in a large animal was published in 2004. In fact, the authors transplanted OECs obtained from pigs, into the lesioned spinal cords of non-human primates. They showed also in this study that OEC transplantation enhances remyelination [97].

In 2004, the first study regarding the effects of OEC transplantation in context of de-
generative diseases was published. Indeed, Agrawal et al. published a study showing that
OEC transplantation can restore deficits induced in an experimental model of Parkinson's
disease [98].

Finally, in 2005, Féron et al. reported the first clinical study in human. In this phase
one clinical trial, autologous OEC transplantation was performed in patients suffering
SCI [99].

**5. Transplantation of OECs after Spinal Cord Injury**

Between one third and half of the publications related to OECs investigated the effects of their transplantation after SCI. Indeed, as mentioned above, since the second half of the nineties the unique properties of OECs have encouraged researchers to use these cells as therapy after various SCI models such as contusion, transection or demyelination. Therefore, the effects of OEC transplantation after SCI are well documented and the positive and negative effects can be discussed.

It is important to note that, even if DRGs are anatomically included in the PNS, a rhizotomy lesion model will be discussed in this section. The fact that axonal regrowth of the sensory axons into the spinal cord is one of the main outcomes of this lesion model, makes it, in our view, an SCI model.

In this section we will differentiate three lesion paradigms: (1) Lesions of the DRG or rhizotomy, as described above, this model should be considered a CNS lesion model, however, the injury site is in the PNS. (2) Traumatic SCI, lesion models regroup contusion and transection, these models are the most widely used SCI models. (3) Demyelinating SCI, in particular irradiation models, these models are mechanistically very informative however, properties and survival of OECs differ from the other SCI models.

Rhizotomy lesion model: this model is very interesting. As described above, it constitutes the first model in which beneficial effects of the transplantation of OECs was reported. Moreover, it appears that this model is the one in which OEC transplantations are least effective. Indeed, the ratio of studies describing beneficial effects and those describing the absence of effects is around 50%. In fact, the first reported studies describe positive effects after transplantation of OECs in the rhizotomy model [29,100]. In contrast, more recent studies report that OEC transplantation has no effect in this lesion model [101–103]. The main difference between these studies is the injection site. Indeed, in the two first studies the OECs were injected into the dorsal root entry zone (DREZ), at the frontier between the PNS and the CNS, whereas at the opposite in the three other studies OECs have been injected into the DRG, in the PNS. These contradictory results seem to indicate that OECs can promote axonal regrowth of the spinal sensory axons when they are injected into the spinal cord but that these cells cannot migrate from the PNS to the CNS through the
DREZ when they are injected into the PNS. Other research team have reported contradictory results in this model. Ibrahim et al. reported that OB-OECs can induce axonal regrowth after transplantation but that OM-OECs cannot in the same lesion and transplantation model [104,105]. In these publications, primary OECs cultures have been injected. The difference in the ratio of OECs to fibroblasts could explain the different results reported. As described in Section 3, primary OM cultures contain only 5 to 10% OECs.

Traumatic SCI: Most of the investigations regarding the effects of OECs transplantation have been conducted after traumatic SCI. Therefore, many reviews and meta-analysis articles have summarized the results induced by OEC transplantations [43,106,107]. Based on the different articles and meta-analyses published, we can build an objective picture of the effects of OEC transplantation in this context. Indeed, since the first studies from the second half of the 1990s, it appears that in the vast majority of the cases, OEC transplantation after SCI modulates the lesion scar, enhances axonal regrowth and induces functional recovery [85,92,96,108–112]. Some studies reported that OEC transplantation after SCI does not improve functional recovery even though they modulate the lesion scar [113]. In contrast, some studies have described the absence of effects after OEC transplantation [102,103,114,115]. These contradictory results can be explained by the different experimental conditions. Indeed, OECs can be obtained from OB or from OM and can be transplanted as primary cultures or after purification step(s) [116]. SCI can be induced by contusion or by transection [114,117]. The cells can be transplanted immediately or several days or weeks after SCI [118,119]. The number of transplanted cells is also different between studies. Due to the fact that more than 200 studies have investigated the effects of OEC transplantation after SCI, a transplantation "gold standard" could be established. Indeed, Watzlawick et al. in 2016 published a meta-analysis summarizing the most effective way to transplant OECs after SCI [120]. It appears that the most effective way to transplant OECs in order to enhance functional recovery after SCI is to transplant 100,000 to 200,000 cells obtained from primary OB-OEC cultures immediately in a transection SCI model [120].

Even if the vast majority of the published studies describe positive effects after transplantation of OECs in SCI, side-effects have also been reported. Nakhjavan-Shahraki et al. have analyzed the effects of OECs transplantation on allodynia [121]. In this meta-analysis, they describe that OEC transplantation did not have an effect on this parameter and can even lead to aggravate hyperalgesia [121].

Altogether, OEC transplantation is one of the most effective therapies after SCI, with limited side effects. That is why many studies have tried to understand the main mechanisms to explain the positive results observed (Figure 1d).

The first thing that has been investigated is the survival of OECs after their transplantation in traumatic SCI. To do so, fluorescent positive OECs have been injected into the lesioned spinal cord and immunohistological studies performed at several time points after transplantation. In most of the studies, it appears that the vast majority of the transplanted OECs do not survive after 2 to 4 weeks after transplantation [122]. This does not mean that OECs cannot be found in the lesioned spinal cord parenchyma, but that the percentage of surviving cells is very low, between 1 to 10% one month post transplantation [106]. A recent study investigated the survival of OECs after transplantation in SCI and compared their survival with those of olfactory fibroblasts [117]. They demonstrated that OECs survive longer than fibroblasts [117]. Collectively these results are of primary importance, indeed they indicate that OECs after SCI mainly exert their effect during the first 2 or 4 weeks after transplantation due to the fact that they die over time and cannot be found anymore 2 or 3 months post SCI, even when at these time points functional recovery and tissue repair can be observed in transplanted animals. Therefore, it has been hypothesized that OECs exert their effect in three ways: (1) secretion of trophic factors and modulation of the endogenous cells, (2) protection and stabilization of axons and (3) immunomodulation and phagocytosis (Figure 1d).
DREZ when they are injected into the PNS. Other research team have reported contradictory results in this model. Ibrahim et al. reported that OB-OECs can induce axonal regrowth after transplantation but that OM-OECs cannot in the same lesion and transplantation model [104,105]. In these publications, primary OECs cultures have been injected. The difference in the ratio of OECs to fibroblasts could explain the different results reported. As described in Section 3, primary OM cultures contain only 5 to 10% OECs.

Traumatic SCI: Most of the investigations regarding the effects of OECs transplantation have been conducted after traumatic SCI. Therefore, many reviews and meta-analysis articles have summarized the results induced by OEC transplantations [43,106,107]. Based on the different articles and meta-analyses published, we can build an objective picture of the effects of OEC transplantation in this context. Indeed, since the first studies from the second half of the 1990s, it appears that in the vast majority of the cases, OEC transplantation after SCI modulates the lesion scar, enhances axonal regrowth and induces functional recovery [85,92,96,108–112]. Some studies reported that OEC transplantation after SCI does not improve functional recovery even though they modulate the lesion scar [113]. In contrast, some studies have described the absence of effects after OEC transplantation [102,103,114,115]. These contradictory results can be explained by the different experimental conditions. Indeed, OECs can be obtained from OB or from OM and can be transplanted as primary cultures or after purification step(s) [116]. SCI can be induced by contusion or by transection [114,117]. The cells can be transplanted immediately or several days or weeks after SCI [118,119]. The number of transplanted cells is also different between studies. Due to the fact that more than 200 studies have investigated the effects of OEC transplantation after SCI, a transplantation “gold standard” could be established. Indeed, Watzlawick et al. in 2016 published a meta-analysis summarizing the most effective way to transplant OECs after SCI [120]. It appears that the most effective way to transplant OECs in order to enhance functional recovery after SCI is to transplant 100,000 to 200,000 cells obtained from primary OB-OEC cultures immediately in a transection SCI model [120].

Even if the vast majority of the published studies describe positive effects after transplantation of OECs in SCI, side-effects have also been reported. Nakhjavan-Shahraki et al. have analyzed the effects of OECs transplantation on allodynia [121]. In this meta-analysis, they describe that OEC transplantation did not have an effect on this parameter and can even lead to aggravate hyperalgesia [121].

Altogether, OEC transplantation is one of the most effective therapies after SCI, with limited side effects. That is why many studies have tried to understand the main mechanisms to explain the positive results observed (Figure 1d).

The first thing that has been investigated is the survival of OECs after their transplantation in traumatic SCI. To do so, fluorescent positive OECs have been injected into the lesioned spinal cord and immunohistological studies performed at several time points after transplantation. In most of the studies, it appears that the vast majority of the transplanted OECs do not survive after 2 to 4 weeks after transplantation [122]. This does not mean that OECs cannot be found in the lesioned spinal cord parenchyma, but that the percentage of surviving cells is very low, between 1 to 10% one month post transplantation [106]. A recent study investigated the survival of OECs after transplantation in SCI and compared their survival with those of olfactory fibroblasts [117]. They demonstrated that OECs survive longer than fibroblasts [117]. Collectively these results are of primary importance, indeed they indicate that OECs after SCI mainly exert their effect during the first 2 or 4 weeks after transplantation due to the fact that they die over time and cannot be found anymore 2 or 3 months post SCI, even when at these time points functional recovery and tissue repair can be observed in transplanted animals. Therefore, it has been hypothesized that OECs exert their effect in three ways: (1) secretion of trophic factors and modulation of the endogenous cells, (2) protection and stabilization of axons and (3) immunomodulation and phagocytosis (Figure 1d).
1. In effect, due to the fact that OECs survival is low, the first hypothesis regarding the role played by OEC transplantation after SCI was that they enhance tissue repair and functional recovery by indirect effects such as neurotrophic factors secretion, modulation of the ECM or by recruiting SC into the lesioned spinal cord parenchyma [123,124]. We can summarize this process by the fact that OEC transplantation changes the inhibitory microenvironment which is put in place after SCI for a more favorable one for axonal regrowth and tissue repair. Indeed, as described above many studies have reported that OEC transplantation enhances axonal regrowth after SCI (Figure 1c). However, due to the fact that OECs exert these effects indirectly, the precise mechanisms are not well described. In fact, it has been demonstrated that OECs modulate the expression of chondroitin sulfate proteoglycan (CSPG), which are well known and described as major inhibitory molecules of lesion scarring [112,125]. It is also described that OECs transplantation after SCI enhances myelination [126,127] (Figure 1d). However, the precise role that OECs play after transplantation on astrocytes or oligodendrocytes is not well known. It has been hypothesized that OECs transplantation after SCI enhances SCs infiltration into the injured parenchyma [128]. Nevertheless, this hypothesis seems unlikely, in effect, recently Assinck et al. have demonstrated that P0 positive cells, which can be found in the injured spinal cord after SCI, have their origin in oligodendrocyte progenitor cells [129]. That is why further studies are necessary to understand the precise role played by OECs on endogenous cells such as astrocytes, oligodendrocytes or ependymal cells after SCI.

2. Protection and stabilization of axons has been hypothesized based on the physi-
logical functions of OECs in the POS. Indeed, Li and Raisman have called it the “pathway
hypothesis” [130]. This hypothesis describes that OECs in close association with fibroblasts create an open channel in which axons can regenerate. This hypothesis could also
explain why transplantation of primary a OB-OEC culture containing a mixture of OECs
and olfactory fibroblasts is more efficient than purified OB-OEC transplantation after SCI.
This hypothesis was confirmed later by Khankahn et al., who showed that transplanted
OECs are associated with axons in the lesion core, enhancing axon survival and axonal
regrowth [117] (Figure 1d).

3. Immunomodulation and phagocytosis roles of OECs have been reported more recently. In fact, OECs seem to regulate inflammation by indirect and direct effects. Indeed, OECs can phagocyte PON into the POS, which is why it has been hypothesized that OECs can clear myelin and axon debris at the injury site after SCI [78]. This hypothesis has been confirmed by several studies in vitro and in vivo [76,79,131]. These studies assessed the phagocytic capacities of the OECs and demonstrate that these cells exhibit high capacities for phagocytosis [79]. Based on these particular competences, some authors have defined OECs as “immunocytes” [80]. These direct effects of OECs by phagocytosis on axonal and myelin debris are associated with indirect effects by secretion of immunomodulatory cytokines (Figure 1d). Several studies have demonstrated that OECs can secret anti-inflammatory molecules in vitro and that OECs after transplantation can regulate inflammation in the lesioned spinal cord [79,117]. Indeed, Khankan et al., have demonstrated that OECs after transplantation reduce the infiltration of Iba1 positive cells into the lesion core [117].

Demyelinating SCI: This model is of a particular interest because it has revealed un-
expected specific properties of OECs after their transplantation into the CNS [90,132–135].
This model was reported for the first time in 1996, after which it has been investigated
by other groups [133,136]. This model is a “demyelination-like” model induced by X-ray
irradiation which can be associated with focal ethidium bromide injections. This model
allows to induce loss of sensorimotor functions comparable to those occurring after SCI
without transection of the descending and ascending tracts. In this model, it has been
described that OECs can survive, migrate and form P0 positive myelin around the axons
(Figure 1d). These specific and unexpected properties are not commonly described after
traumatic SCI. In this model, the properties of OECs have been compared to those of the
SCs. It appears that OECs can migrate extensively after transplantation which was not
the case with SCs [134]. Moreover, this study is one of the first to report that OECs can
1. In effect, due to the fact that OECs survival is low, the first hypothesis regarding the role played by OEC transplantation after SCI was that they enhance tissue repair and functional recovery by indirect effects such as neurotrophic factors secretion, modulation of the ECM or by recruiting SC into the lesioned spinal cord parenchyma [123,124]. We can summarize this process by the fact that OEC transplantation changes the inhibitory microenvironment which is put in place after SCI for a more favorable one for axonal regrowth and tissue repair. Indeed, as described above many studies have reported that OEC transplantation enhances axonal regrowth after SCI (Figure 1c). However, due to the fact that OECs exert these effects indirectly, the precise mechanisms are not well described. In fact, it has been demonstrated that OECs modulate the expression of chondroitin sulfate proteoglycan (CSPG), which are well known and described as major inhibitory molecules of lesion scarring [112,125]. It is also described that OECs transplantation after SCI enhances myelination [126,127] (Figure 1d). However, the precise role that OECs play after transplantation on astrocytes or oligodendrocytes is not well known. It has been hypothesized that OECs transplantation after SCI enhances SCs infiltration into the injured parenchyma [128]. Nevertheless, this hypothesis seems unlikely, in effect, recently Assinck et al. have demonstrated that P0 positive cells, which can be found in the injured spinal cord after SCI, have their origin in oligodendrocyte progenitor cells [129]. That is why further studies are necessary to understand the precise role played by OECs on endogenous cells such as astrocytes, oligodendrocytes or ependymal cells after SCI.

2. Protection and stabilization of axons has been hypothesized based on the physi-
logical functions of OECs in the POS. Indeed, Li and Raisman have called it the “pathway
hypothesis” [130]. This hypothesis describes that OECs in close association with fibroblasts create an open channel in which axons can regenerate. This hypothesis could also
explain why transplantation of primary a OB-OEC culture containing a mixture of OECs
and olfactory fibroblasts is more efficient than purified OB-OEC transplantation after SCI.
This hypothesis was confirmed later by Khankahn et al., who showed that transplanted
OECs are associated with axons in the lesion core, enhancing axon survival and axonal
regrowth [117] (Figure 1d).

3. Immunomodulation and phagocytosis roles of OECs have been reported more recently. In fact, OECs seem to regulate inflammation by indirect and direct effects. Indeed, OECs can phagocyte PON into the POS, which is why it has been hypothesized that OECs can clear myelin and axon debris at the injury site after SCI [78]. This hypothesis has been confirmed by several studies in vitro and in vivo [76,79,131]. These studies assessed the phagocytic capacities of the OECs and demonstrate that these cells exhibit high capacities for phagocytosis [79]. Based on these particular competences, some authors have defined OECs as “immunocytes” [80]. These direct effects of OECs by phagocytosis on axonal and myelin debris are associated with indirect effects by secretion of immunomodulatory cytokines (Figure 1d). Several studies have demonstrated that OECs can secret anti-inflammatory molecules in vitro and that OECs after transplantation can regulate inflammation in the lesioned spinal cord [79,117]. Indeed, Khankan et al., have demonstrated that OECs after transplantation reduce the infiltration of Iba1 positive cells into the lesion core [117].

Demyelinating SCI: This model is of a particular interest because it has revealed un-
expected specific properties of OECs after their transplantation into the CNS [90,132–135].
This model was reported for the first time in 1996, after which it has been investigated
by other groups [133,136]. This model is a “demyelination-like” model induced by X-ray
irradiation which can be associated with focal ethidium bromide injections. This model
allows to induce loss of sensorimotor functions comparable to those occurring after SCI
without transection of the descending and ascending tracts. In this model, it has been
described that OECs can survive, migrate and form P0 positive myelin around the axons
(Figure 1d). These specific and unexpected properties are not commonly described after
traumatic SCI. In this model, the properties of OECs have been compared to those of the
SCs. It appears that OECs can migrate extensively after transplantation which was not
the case with SCs [134]. Moreover, this study is one of the first to report that OECs can
express phagocytic properties [134] (Figure 1d). More recently, the same research group has conducted a study regarding the properties of OECs and SCs in an irradiation-related context, in a brain injury model [136]. In this study, the brains of three-week-old rats were irradiated, and one week later, OECs and SCs were transplanted into their hippocampus. It appears, that in this model, OECs can survive and migrate, but can also proliferate. Indeed, Ki67 staining reveals that some transplanted OECs are still dividing 3 weeks after transplantation [136]. As previously reported in demyelinated spinal cord, in irradiated brains, OECs express phagocytic abilities according to their expression of OX-42 [136].

**6. Transplantation of OECs after Peripheral Nerve Injury**

Even though OEC transplantations have mainly been applied after SCI, numerous studies have investigated the effects of OECs after peripheral nerve injury (PNI). Indeed, as described above, the first reported study regarding OECs transplantation after PNI was published in 1999 [93]. The effects of OECs after PNI have been assessed in different lesion models. The vast majority of these studies have been performed using SN [137–142]. Different lesion paradigms have been used, such as complete transection or crush injury. It has been demonstrated that OEC transplantation induces axonal regrowth and functional recovery (Figure 1d). More interestingly, in a crush injury model, Dombrowski et al. demonstrated that OECs can survive until 6 months after transplantation and form functional myelin with nodes of Ranvier in which sodium channels can be found [143].

Several studies have been performed using cranial nerve injury models such as facial nerve or optic nerve [142]. In 2001 and 2002, Guntinas-Lichius et al., demonstrated that in facial nerve injury models, transplantation of OECs enhances axonal regrowth and functional recovery of the vibrissae [144,145]. Moreover, in these studies the authors performed retrograde labeling, allowing to highlight muscular co-contraction phenomenon, called synkinesis. To do so, they injected several retrograde tracers into three different facial muscles in order to demonstrate the specificity of the nerve–target muscle connections. They demonstrated that OEC transplantation increases the selectivity of the axonal regrowth and decreases the synkinesis [144,145] (Figure 1d).

Several studies have investigated the effects of OECs transplantation after optic nerve injury. The first study was performed by Li et al. in 2003. They showed that OEC transplantation after a transection of the optic nerve allows axonal regrowth of the retinal ganglion cells [146]. Interestingly, they also showed, in another study, that OECs in this model do not form myelin but ensheathe bundles of axons, whereas in contrast, in the same lesion model transplanted SCs myelinate optic nerve axons [147] (Figure 1d).

A few studies have been also performed after vagus or recurrent laryngeal nerve injuries. In these models, OEC transplantation also induced tissue repair and functional recovery. Based on vocal cord movement analysis the authors demonstrated that OEC transplantation reduces aberrant movements [148,149] (Figure 1d).

In contrast to the SCI, there is no study showing an absence of positive effects after transplantation of OECs in PNI context. Indeed, all the published studies demonstrate that OEC transplantation after PNI enhances tissue repair, axonal regrowth or myelination, and in the vast majority, induces functional recovery.

Some comparative studies demonstrate that according to their origin, OECs can exert different effects. Indeed, it has been demonstrated that transplantation of primary cultures of OECs obtained from OM do not significantly enhance axonal regrowth and functional recovery in a vagus nerve injury model in comparison to the transplantation of primary cultures of OECs obtained from OB [148]. Beyond the different expression profiles of the OECs according to their respective origin, these differences can be also explained by the low amount of OECs in primary OM cultures which is around 5 to 10% in comparison to the ratio of OECs in primary OB cultures which is around 50%.

We described above that after traumatic SCI, OECs mainly exert their beneficial effects within the two first weeks after transplantation. In contrast, it seems that after transplantation in PNI context, OECs can be integrated in the regenerative tissues. Indeed,
express phagocytic properties [134] (Figure 1d). More recently, the same research group has conducted a study regarding the properties of OECs and SCs in an irradiation-related context, in a brain injury model [136]. In this study, the brains of three-week-old rats were irradiated, and one week later, OECs and SCs were transplanted into their hippocampus. It appears, that in this model, OECs can survive and migrate, but can also proliferate. Indeed, Ki67 staining reveals that some transplanted OECs are still dividing 3 weeks after transplantation [136]. As previously reported in demyelinated spinal cord, in irradiated brains, OECs express phagocytic abilities according to their expression of OX-42 [136].

**6. Transplantation of OECs after Peripheral Nerve Injury**

Even though OEC transplantations have mainly been applied after SCI, numerous studies have investigated the effects of OECs after peripheral nerve injury (PNI). Indeed, as described above, the first reported study regarding OECs transplantation after PNI was published in 1999 [93]. The effects of OECs after PNI have been assessed in different lesion models. The vast majority of these studies have been performed using SN [137–142]. Different lesion paradigms have been used, such as complete transection or crush injury. It has been demonstrated that OEC transplantation induces axonal regrowth and functional recovery (Figure 1d). More interestingly, in a crush injury model, Dombrowski et al. demonstrated that OECs can survive until 6 months after transplantation and form functional myelin with nodes of Ranvier in which sodium channels can be found [143].

Several studies have been performed using cranial nerve injury models such as facial nerve or optic nerve [142]. In 2001 and 2002, Guntinas-Lichius et al., demonstrated that in facial nerve injury models, transplantation of OECs enhances axonal regrowth and functional recovery of the vibrissae [144,145]. Moreover, in these studies the authors performed retrograde labeling, allowing to highlight muscular co-contraction phenomenon, called synkinesis. To do so, they injected several retrograde tracers into three different facial muscles in order to demonstrate the specificity of the nerve–target muscle connections. They demonstrated that OEC transplantation increases the selectivity of the axonal regrowth and decreases the synkinesis [144,145] (Figure 1d).

Several studies have investigated the effects of OECs transplantation after optic nerve injury. The first study was performed by Li et al. in 2003. They showed that OEC transplantation after a transection of the optic nerve allows axonal regrowth of the retinal ganglion cells [146]. Interestingly, they also showed, in another study, that OECs in this model do not form myelin but ensheathe bundles of axons, whereas in contrast, in the same lesion model transplanted SCs myelinate optic nerve axons [147] (Figure 1d).

A few studies have been also performed after vagus or recurrent laryngeal nerve injuries. In these models, OEC transplantation also induced tissue repair and functional recovery. Based on vocal cord movement analysis the authors demonstrated that OEC transplantation reduces aberrant movements [148,149] (Figure 1d).

In contrast to the SCI, there is no study showing an absence of positive effects after transplantation of OECs in PNI context. Indeed, all the published studies demonstrate that OEC transplantation after PNI enhances tissue repair, axonal regrowth or myelination, and in the vast majority, induces functional recovery.

Some comparative studies demonstrate that according to their origin, OECs can exert different effects. Indeed, it has been demonstrated that transplantation of primary cultures of OECs obtained from OM do not significantly enhance axonal regrowth and functional recovery in a vagus nerve injury model in comparison to the transplantation of primary cultures of OECs obtained from OB [148]. Beyond the different expression profiles of the OECs according to their respective origin, these differences can be also explained by the low amount of OECs in primary OM cultures which is around 5 to 10% in comparison to the ratio of OECs in primary OB cultures which is around 50%.

We described above that after traumatic SCI, OECs mainly exert their beneficial effects within the two first weeks after transplantation. In contrast, it seems that after transplantation in PNI context, OECs can be integrated in the regenerative tissues. Indeed,
OECs can survive several months after crush injury of the SN and can form peripheral-like P0 myelin [143]. Additionally to these direct effects on axonal survival, regrowth and myelination, OECs also have positive effects in an indirect manner by secretion of trophic factors, as described after their transplantation in an SCI context [150].

## 7. OECs Transplantation in Other CNS Injury Models

The properties of OECs have been studied in other pathological models and human diseases. In this section, studies conducted in animal models and human studies will be presented.

OECs properties have been investigated in a Parkinson's model (Figure 1d). To do so, authors induced the disease by injection of 6-hydroxydopamine into the substantia nigra of rats [151]. Thereafter, OECs were grafted into the striatum. In this model, the authors did not observe an improvement in the transplanted group [151]. In contrast, using the same lesion model, Agrawal et al. demonstrated that the co-transplantation of OECs with fetal ventral mesencephalic cells (VMC) increases survival of these cells and exhibits better motor recovery compared to the rats receiving VMC transplantation alone [98]. Authors highlight that OECs probably promote the elongation of dopaminergic and serotonergic axons in addition to improving survival [98,152].

OECs were tested in hippocampal lesion models induced by carbon monoxide [153] or kainic acid [154] (Figure 1d). In the first model, it was demonstrated that OEC transplantation decreases oxidative stress and apoptosis in the hippocampus, reduces cerebral edema in rats and improves neurological function [153]. In the second model the authors decided to transplant OECs in addition to neural progenitor cells (NPC). Interestingly, transplantation of OECs or NPCs alone shows efficacy in improving learning and memory; however, co-transplantation of these two cell types significantly enhances tissue repair over transplantation of OECs or NPCs alone [154]. These two studies underline the major role played by neurotrophic factor release of OECs on NPC survival [154].

Traumatic brain injury (TBI) is a frequent pathology that can be very disabling. For the last decade, researchers have been trying to find effective therapies. That is why some studies have investigated the effects of OEC transplantation after TBI (Figure 1d). In 2014, Wang et al. demonstrated that OEC transplantation in a contusive TBI model improves neurological severity score (NSS), based on motor ability, balancing and alertness. This improvement is correlated with an increase in GAP-43 fibers and synaptophysin vesicles, generally considered to be markers of neuronal plasticity [155]. Moreover, in the same study the authors demonstrate that OEC transplantation downregulates BAD expression, which is a transcription factor implicated in apoptosis [155]. Other teams have evaluated the effects of OEC transplantation in association with other cell types in a TBI model. In effect, OEC transplantation has been combined with bone mesenchymal stem cells (BMSC) after contusive TBI [156]. The results obtained by Fu et al. confirm those described in the Wang et al. study. In fact, NSS was improved in the OEC and BMSC groups but the maximum efficiency was obtained in the co-transplanted group (OECs + BMSC group). The authors highlight the Janus kinase/signal transducer and activator of transcription pathway, as a signaling pathway involved in these therapeutic effects [156]. Liu et al. have combined OECs with NSC. Their results show a reduction in BAD signaling, as described previously by Wang et al. [155], but also a decrease in IL-6 expression at the lesion site [157]. These effects are observed in each transplanted cell group but co-transplantation leads to better effects in comparison to the other groups [157]. Interestingly, the same co-transplantation has been tested in retinal degenerative disease [158]. This study results show that co-transplantation induces beneficial effects by decreasing reactive gliosis of Müller cells after retina damage [158].

Two studies based on the stroke model have investigated the effects of OEC transplantation (Figure 1d). The first one studied the effects on OEC transplantation in a middle cerebral artery occlusion (MCAO) model [159]. Researchers show that OEC transplantation reduces infarct volume and increases neurological score and tissue repair 56 days
OECs can survive several months after crush injury of the SN and can form peripheral-like P0 myelin [143]. Additionally to these direct effects on axonal survival, regrowth and myelination, OECs also have positive effects in an indirect manner by secretion of trophic factors, as described after their transplantation in an SCI context [150].

## 7. OECs Transplantation in Other CNS Injury Models

The properties of OECs have been studied in other pathological models and human diseases. In this section, studies conducted in animal models and human studies will be presented.

OECs properties have been investigated in a Parkinson's model (Figure 1d). To do so, authors induced the disease by injection of 6-hydroxydopamine into the substantia nigra of rats [151]. Thereafter, OECs were grafted into the striatum. In this model, the authors did not observe an improvement in the transplanted group [151]. In contrast, using the same lesion model, Agrawal et al. demonstrated that the co-transplantation of OECs with fetal ventral mesencephalic cells (VMC) increases survival of these cells and exhibits better motor recovery compared to the rats receiving VMC transplantation alone [98]. Authors highlight that OECs probably promote the elongation of dopaminergic and serotonergic axons in addition to improving survival [98,152].

OECs were tested in hippocampal lesion models induced by carbon monoxide [153] or kainic acid [154] (Figure 1d). In the first model, it was demonstrated that OEC transplantation decreases oxidative stress and apoptosis in the hippocampus, reduces cerebral edema in rats and improves neurological function [153]. In the second model the authors decided to transplant OECs in addition to neural progenitor cells (NPC). Interestingly, transplantation of OECs or NPCs alone shows efficacy in improving learning and memory; however, co-transplantation of these two cell types significantly enhances tissue repair over transplantation of OECs or NPCs alone [154]. These two studies underline the major role played by neurotrophic factor release of OECs on NPC survival [154].

Traumatic brain injury (TBI) is a frequent pathology that can be very disabling. For the last decade, researchers have been trying to find effective therapies. That is why some studies have investigated the effects of OEC transplantation after TBI (Figure 1d). In 2014, Wang et al. demonstrated that OEC transplantation in a contusive TBI model improves neurological severity score (NSS), based on motor ability, balancing and alertness. This improvement is correlated with an increase in GAP-43 fibers and synaptophysin vesicles, generally considered to be markers of neuronal plasticity [155]. Moreover, in the same study the authors demonstrate that OEC transplantation downregulates BAD expression, which is a transcription factor implicated in apoptosis [155]. Other teams have evaluated the effects of OEC transplantation in association with other cell types in a TBI model. In effect, OEC transplantation has been combined with bone mesenchymal stem cells (BMSC) after contusive TBI [156]. The results obtained by Fu et al. confirm those described in the Wang et al. study. In fact, NSS was improved in the OEC and BMSC groups but the maximum efficiency was obtained in the co-transplanted group (OECs + BMSC group). The authors highlight the Janus kinase/signal transducer and activator of transcription pathway, as a signaling pathway involved in these therapeutic effects [156]. Liu et al. have combined OECs with NSC. Their results show a reduction in BAD signaling, as described previously by Wang et al. [155], but also a decrease in IL-6 expression at the lesion site [157]. These effects are observed in each transplanted cell group but co-transplantation leads to better effects in comparison to the other groups [157]. Interestingly, the same co-transplantation has been tested in retinal degenerative disease [158]. This study results show that co-transplantation induces beneficial effects by decreasing reactive gliosis of Müller cells after retina damage [158].

Two studies based on the stroke model have investigated the effects of OEC transplantation (Figure 1d). The first one studied the effects on OEC transplantation in a middle cerebral artery occlusion (MCAO) model [159]. Researchers show that OEC transplantation reduces infarct volume and increases neurological score and tissue repair 56 days
after MCAO. These results are also associated with a reduction in mortality in the OEC-
transplanted group [159]. The second study is based on an intracerebral hemorrhage model.
Here, OECs were transplanted with NSC and serve as trophic support for NSC survival
and differentiation. The authors highlight that co-transplantation decreases neurological
deficit score from 14 days, whereas the transplantation of each of these cell types alone
brings the effect from 30 days. They explain this difference by a better survival, migration,
and differentiation of NSCs into neurons, astrocytes and oligodendrocytes in the presence
of OECs [160].

Finally, another interesting application of OECs in an animal model was reported
by Carvalho et al. In this study OECs were used to transport and to deliver transgenes
to glioblastoma cells. Authors have injected OECs into the nasal cavity and OECs have
migrated to glioblastoma inducing slower tumor growth and increased mice survival [161].

All the studies described above showed beneficial effect after transplantation or co-
transplantation of OECs. However, several studies have investigated the effects of OEC
transplantation in amyotrophic lateral sclerosis (ALS). These studies reported mitigating
effects of OECs in animal studies as well as in clinical studies.

In effect, several studies conducted on human showed opposite results in terms of
beneficial effects of OEC transplantation. The first study, based on 327 patients, demon-
strated that OEC transplantation in the spinal cord and/or bilateral corona radiata of the
frontal lobes provided improvement or stabilization of the pathology. To demonstrate
the results, patients were assessed on the ALS-Functional Rating Scale (ALS-FRS) [162].
However, other studies wanted to reproduce these beneficial effects. Based on the same
protocol but using fetal OECs, a second study on 14 patients was conducted and showed
that seven patients had neurological improvement, two were stabilized and five presented
a decrease in their ALS-FRS score [163]. In an animal study, Morita et al., demonstrated
in an ALS mouse model that OEC transplantation has no positive effect [164]. This was
confirmed in human by an Italian team who studied the post-mortem brains of two ALS
patients who had received OECs. They did not find any evidence of axonal regeneration,
neuronal differentiation and myelination in connection with the OEC transplantation [165].
Finally, another study of OECs transplantation in ALS patients prospectively followed
seven patients before and after treatment. Despite subjective positive effects directly af-
ter treatment in three patients, no individual objective improvement was measured, and
outcome measurements gradually declined in all patients [166].

Chen et al. were the only ones to test OECs in human cerebral palsy. They performed
bilateral transplants into the corona radiata in the frontal lobes with human fetal OECs in
patients ranging from 1 to 12 years old. They showed that there is no side effect related to
the transplant and that patients of OECs group got better Gross Motor Function Measure
scores than control [167].

8. Future Directions

As we tried to demonstrate in this review, OEC transplantation enhances tissue repair and functional recovery in the majority of the lesion models studied. Although these abilities make OECs a unique cell type, several studies have tried to potentiate OECs properties or to associate OECs with other therapies or even to skirt some limitations which are intrinsically related to cellular transplantation.

Indeed, in 2002, Ruitenbergh et al. reported for the first time that OECs’ gene expression
can be modified by adeno or lenti viruses [168]. Thereafter several studies investigated the
effects of genetically-modified OEC transplantation after SCI [122,169–171]. To our knowl-
edge, the first one was published in 2004; in this study Cao et al., report that transplantation
of OECs genetically modified to secrete GDNF improves functional recovery after SCI [169].
These studies tried to enhance one specific ability of the OECs: secretion of trophic factors
and ECM molecules. Collectively, they report that genetically enhanced OECs improve
functional recovery and tissue repair.
after MCAO. These results are also associated with a reduction in mortality in the OEC-
transplanted group [159]. The second study is based on an intracerebral hemorrhage model.
Here, OECs were transplanted with NSC and serve as trophic support for NSC survival
and differentiation. The authors highlight that co-transplantation decreases neurological
deficit score from 14 days, whereas the transplantation of each of these cell types alone
brings the effect from 30 days. They explain this difference by a better survival, migration,
and differentiation of NSCs into neurons, astrocytes and oligodendrocytes in the presence
of OECs [160].

Finally, another interesting application of OECs in an animal model was reported
by Carvalho et al. In this study OECs were used to transport and to deliver transgenes
to glioblastoma cells. Authors have injected OECs into the nasal cavity and OECs have
migrated to glioblastoma inducing slower tumor growth and increased mice survival [161].

All the studies described above showed beneficial effect after transplantation or co-
transplantation of OECs. However, several studies have investigated the effects of OEC
transplantation in amyotrophic lateral sclerosis (ALS). These studies reported mitigating
effects of OECs in animal studies as well as in clinical studies.

In effect, several studies conducted on human showed opposite results in terms of
beneficial effects of OEC transplantation. The first study, based on 327 patients, demon-
strated that OEC transplantation in the spinal cord and/or bilateral corona radiata of the
frontal lobes provided improvement or stabilization of the pathology. To demonstrate
the results, patients were assessed on the ALS-Functional Rating Scale (ALS-FRS) [162].
However, other studies wanted to reproduce these beneficial effects. Based on the same
protocol but using fetal OECs, a second study on 14 patients was conducted and showed
that seven patients had neurological improvement, two were stabilized and five presented
a decrease in their ALS-FRS score [163]. In an animal study, Morita et al., demonstrated
in an ALS mouse model that OEC transplantation has no positive effect [164]. This was
confirmed in human by an Italian team who studied the post-mortem brains of two ALS
patients who had received OECs. They did not find any evidence of axonal regeneration,
neuronal differentiation and myelination in connection with the OEC transplantation [165].
Finally, another study of OECs transplantation in ALS patients prospectively followed
seven patients before and after treatment. Despite subjective positive effects directly af-
ter treatment in three patients, no individual objective improvement was measured, and
outcome measurements gradually declined in all patients [166].

Chen et al. were the only ones to test OECs in human cerebral palsy. They performed
bilateral transplants into the corona radiata in the frontal lobes with human fetal OECs in
patients ranging from 1 to 12 years old. They showed that there is no side effect related to
the transplant and that patients of OECs group got better Gross Motor Function Measure
scores than control [167].

8. Future Directions

As we tried to demonstrate in this review, OEC transplantation enhances tissue repair and functional recovery in the majority of the lesion models studied. Although these abilities make OECs a unique cell type, several studies have tried to potentiate OECs properties or to associate OECs with other therapies or even to skirt some limitations which are intrinsically related to cellular transplantation.

Indeed, in 2002, Ruitenbergh et al. reported for the first time that OECs’ gene expression
can be modified by adeno or lenti viruses [168]. Thereafter several studies investigated the
effects of genetically-modified OEC transplantation after SCI [122,169–171]. To our knowl-
edge, the first one was published in 2004; in this study Cao et al., report that transplantation
of OECs genetically modified to secrete GDNF improves functional recovery after SCI [169].
These studies tried to enhance one specific ability of the OECs: secretion of trophic factors
and ECM molecules. Collectively, they report that genetically enhanced OECs improve
functional recovery and tissue repair.
Another way to improve OECs' effects after transplantation is to associate them with other cell types. Interestingly, as described in part 7, many studies have reported the co-transplantation of OECs and additional cells in numerous lesion models such as PNI, SCI, Parkinson lesion model, hippocampus lesion model, intracerebral hemorrhage model or TBI [142,149,154,156,157,160,172-174]. Mainly, OECs have been transplanted in addition to three different cell types: stem cells, SCs and differentiated neurons. Indeed, the vast majority of the "co-transplantation" studies have investigated the effects of co-grafts of OECs with stem cells such as adipose stem cells, neural stem cells or bone marrow stem cells [175-178]. Co-transplantation of OECs and SCs has also been widely investigated [142,173,179]. Finally, few studies have assessed the effects of co-grafts of OECs with neurons or neuron-derived stem cells [172,180]. Only one study reports the absence of beneficial effects after co-transplantation of OECs and mesenchymal stromal cells (MSC) [181]. In this publication, the authors found that all transplanted groups (OECs, MSC and OECs + MSC) showed enhancement of their functional recovery but without differences between groups. With the exception of this study, all the other published works show additional effects of the co-transplantations, independently of the nature of the co-grafted cells. The expected benefits of such co-transplantations are specific to the co-transplanted cells. Indeed, when OECs are co-transplanted with SCs, the purpose is to combine the properties of the two cellular types. Whereas, the main aim in co-grafting OECs with stem cells or neurons is to use the release of secreting factors by OECs to enhance the survival and integration of the co-transplanted cells; stem cells or neurons.

Another approach which has been widely explored, is to combine OEC transplantation with additional exogenous molecules or with biomaterials. The first reported studies investigated the behaviors of OECs with chondroitinase of cAMP in vivo after SCI [182,183]. These studies report additional functional benefits in the co-grafted groups. One study assessed the effects of complex co-transplantation of SCs and OECs with the addition of chondroitinase pumps and demonstrated that this strategy induces functional recovery after SCI in rats [184].

The co-transplantation of OECs with different biomaterials such as: chitosan polymers, electrospun nanofibers or collagen scaffolds has been also investigated first in vitro [80,175,185-188]. Secondly, these combined therapies have been used to enhance axonal regrowth and functional recovery mainly after PNI or SCI in vivo [189-192]. In all these studies, it appears that the co-administration of OECs with biomaterials induces beneficial effects. More recently, these co-transplantation of OECs and biomaterials studies have also investigated the effects of the injection of microencapsulated OECs after SN injury in rats [193,194]. In these studies, OECs were encapsulated in alginate biogel and then transplanted in the SN after injury. The studies demonstrate that encapsulated OEC administration decreases nociception in this lesion model.

Recently, a new paradigm related to cellular therapy has been proposed and tested after injury. One of the main limitations of cellular therapy is that ideally cells should be transplanted as an autograft in order to limit the transplant rejection. To skirt this limitation, extracellular vesicle transplantation has emerged as a new and promising therapy. As such, OEC extracellular vesicles (OEC-EVs) properties have been assessed in vitro and in vivo. To date, two studies have demonstrated in vitro that OEC-EVs in co-culture with NPC display neuroprotective effects [195,196]. In the same way, one study has investigated the effects of OEC-EVs after PNI and demonstrated that OEC-EVs, when transplanted in an artificial nerve conduit, enhance nerve regeneration and functional recovery after transection of the SN [197]. Another limitation of cellular transplantation is this invasiveness. In fact, transplanted cells are mainly injected into the spinal cord parenchyma. Therefore, the effects of intravenous transplantation of OECs have been investigated. Two studies have demonstrated that intravenous administration of OECs can induce functional recovery and tissue repair by reducing neuroinflammation after SCI [85,198].

Lastly, in order to enhance the survival rate of OECs, which is very low after SCI, OEC transplantation has been combined with repetitive magnetic stimulation (RMS) [199]. This
Another way to improve OECs' effects after transplantation is to associate them with other cell types. Interestingly, as described in part 7, many studies have reported the co-transplantation of OECs and additional cells in numerous lesion models such as PNI, SCI, Parkinson lesion model, hippocampus lesion model, intracerebral hemorrhage model or TBI [142,149,154,156,157,160,172-174]. Mainly, OECs have been transplanted in addition to three different cell types: stem cells, SCs and differentiated neurons. Indeed, the vast majority of the "co-transplantation" studies have investigated the effects of co-grafts of OECs with stem cells such as adipose stem cells, neural stem cells or bone marrow stem cells [175-178]. Co-transplantation of OECs and SCs has also been widely investigated [142,173,179]. Finally, few studies have assessed the effects of co-grafts of OECs with neurons or neuron-derived stem cells [172,180]. Only one study reports the absence of beneficial effects after co-transplantation of OECs and mesenchymal stromal cells (MSC) [181]. In this publication, the authors found that all transplanted groups (OECs, MSC and OECs + MSC) showed enhancement of their functional recovery but without differences between groups. With the exception of this study, all the other published works show additional effects of the co-transplantations, independently of the nature of the co-grafted cells. The expected benefits of such co-transplantations are specific to the co-transplanted cells. Indeed, when OECs are co-transplanted with SCs, the purpose is to combine the properties of the two cellular types. Whereas, the main aim in co-grafting OECs with stem cells or neurons is to use the release of secreting factors by OECs to enhance the survival and integration of the co-transplanted cells; stem cells or neurons.

Another approach which has been widely explored, is to combine OEC transplantation with additional exogenous molecules or with biomaterials. The first reported studies investigated the behaviors of OECs with chondroitinase of cAMP in vivo after SCI [182,183]. These studies report additional functional benefits in the co-grafted groups. One study assessed the effects of complex co-transplantation of SCs and OECs with the addition of chondroitinase pumps and demonstrated that this strategy induces functional recovery after SCI in rats [184].

The co-transplantation of OECs with different biomaterials such as: chitosan polymers, electrospun nanofibers or collagen scaffolds has been also investigated first in vitro [80,175,185-188]. Secondly, these combined therapies have been used to enhance axonal regrowth and functional recovery mainly after PNI or SCI in vivo [189-192]. In all these studies, it appears that the co-administration of OECs with biomaterials induces beneficial effects. More recently, these co-transplantation of OECs and biomaterials studies have also investigated the effects of the injection of microencapsulated OECs after SN injury in rats [193,194]. In these studies, OECs were encapsulated in alginate biogel and then transplanted in the SN after injury. The studies demonstrate that encapsulated OEC administration decreases nociception in this lesion model.

Recently, a new paradigm related to cellular therapy has been proposed and tested after injury. One of the main limitations of cellular therapy is that ideally cells should be transplanted as an autograft in order to limit the transplant rejection. To skirt this limitation, extracellular vesicle transplantation has emerged as a new and promising therapy. As such, OEC extracellular vesicles (OEC-EVs) properties have been assessed in vitro and in vivo. To date, two studies have demonstrated in vitro that OEC-EVs in co-culture with NPC display neuroprotective effects [195,196]. In the same way, one study has investigated the effects of OEC-EVs after PNI and demonstrated that OEC-EVs, when transplanted in an artificial nerve conduit, enhance nerve regeneration and functional recovery after transection of the SN [197]. Another limitation of cellular transplantation is this invasiveness. In fact, transplanted cells are mainly injected into the spinal cord parenchyma. Therefore, the effects of intravenous transplantation of OECs have been investigated. Two studies have demonstrated that intravenous administration of OECs can induce functional recovery and tissue repair by reducing neuroinflammation after SCI [85,198].

Lastly, in order to enhance the survival rate of OECs, which is very low after SCI, OEC transplantation has been combined with repetitive magnetic stimulation (RMS) [199]. This
study demonstrates that RMS treatment does not enhance OEC survival after transplantation in the injured spinal cord and that the combination of the two therapies does not induce any additional benefit.

Finally, as discussed above, one study assessed the potential that OECs could have to deliver therapeutic transgenes through the nasal pathway. In this study, researchers demonstrated that OECs can migrate from the PNS to the CNS and be used as a vector to deliver antitumor drugs to the brain [161].

To conclude: very few cell types possess the same properties as OECs and the same ability to improve tissue repair and functional recovery in such wide range of injury models. That is why we can hope that the few limitations regarding their use in clinical, notably the invasiveness of the biopsy needed to obtain OB-OECs, could be overcome in the near future, allowing their transplantation after CNS or PNS injury.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

**Abbreviations**

<table><tr><td>ALS</td><td>amyotrophic lateral sclerosis</td></tr><tr><td>BMSC</td><td>bone mesenchymal stem cells</td></tr><tr><td>CNS</td><td>central nervous system</td></tr><tr><td>CSPG</td><td>chondroitin sulfate proteoglycan</td></tr><tr><td>CST</td><td>corticospinal tract</td></tr><tr><td>CXCCL</td><td>C-X-C motif chemokine ligand</td></tr><tr><td>DREZ</td><td>dorsal root entry zone</td></tr><tr><td>DRG</td><td>dorsal root ganglion</td></tr><tr><td>ECM</td><td>extracellular matrix</td></tr><tr><td>FRS</td><td>functional rating scale</td></tr><tr><td>MCAO</td><td>middle cerebral artery occlusion</td></tr><tr><td>MIF</td><td>migration inhibitory factor</td></tr><tr><td>MSC</td><td>mesenchymal stromal cells</td></tr><tr><td>NPC</td><td>neural progenitor cells</td></tr><tr><td>NPY</td><td>neuropeptide Y</td></tr><tr><td>NSS</td><td>neurological severity score</td></tr><tr><td>OB</td><td>olfactory bulb</td></tr><tr><td>OE</td><td>olfactory epithelium</td></tr><tr><td>OECs</td><td>olfactory ensheathing cells</td></tr><tr><td>ONL</td><td>outer nerve layer</td></tr><tr><td>PNI</td><td>peripheral nerve injury</td></tr><tr><td>PNS</td><td>peripheral nervous system</td></tr><tr><td>PON</td><td>primary olfactory neuron</td></tr><tr><td>POS</td><td>primary olfactory system</td></tr><tr><td>RMS</td><td>repetitive magnetic stimulation</td></tr><tr><td>SCs</td><td>Schwann cells</td></tr><tr><td>SCI</td><td>spinal cord injury</td></tr><tr><td>SN</td><td>sciatic nerve</td></tr><tr><td>VMC</td><td>ventral mesencephalic cells</td></tr><tr><td>TBI</td><td>traumatic brain injury</td></tr><tr><td>TNF-α</td><td>tumor necrosis factors alpha</td></tr></table>
study demonstrates that RMS treatment does not enhance OEC survival after transplantation in the injured spinal cord and that the combination of the two therapies does not induce any additional benefit.

Finally, as discussed above, one study assessed the potential that OECs could have to deliver therapeutic transgenes through the nasal pathway. In this study, researchers demonstrated that OECs can migrate from the PNS to the CNS and be used as a vector to deliver antitumor drugs to the brain [161].

To conclude: very few cell types possess the same properties as OECs and the same ability to improve tissue repair and functional recovery in such wide range of injury models. That is why we can hope that the few limitations regarding their use in clinical, notably the invasiveness of the biopsy needed to obtain OB-OECs, could be overcome in the near future, allowing their transplantation after CNS or PNS injury.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

**Abbreviations**

<table><tr><td>ALS</td><td>amyotrophic lateral sclerosis</td></tr><tr><td>BMSC</td><td>bone mesenchymal stem cells</td></tr><tr><td>CNS</td><td>central nervous system</td></tr><tr><td>CSPG</td><td>chondroitin sulfate proteoglycan</td></tr><tr><td>CST</td><td>corticospinal tract</td></tr><tr><td>CXCCL</td><td>C-X-C motif chemokine ligand</td></tr><tr><td>DREZ</td><td>dorsal root entry zone</td></tr><tr><td>DRG</td><td>dorsal root ganglion</td></tr><tr><td>ECM</td><td>extracellular matrix</td></tr><tr><td>FRS</td><td>functional rating scale</td></tr><tr><td>MCAO</td><td>middle cerebral artery occlusion</td></tr><tr><td>MIF</td><td>migration inhibitory factor</td></tr><tr><td>MSC</td><td>mesenchymal stromal cells</td></tr><tr><td>NPC</td><td>neural progenitor cells</td></tr><tr><td>NPY</td><td>neuropeptide Y</td></tr><tr><td>NSS</td><td>neurological severity score</td></tr><tr><td>OB</td><td>olfactory bulb</td></tr><tr><td>OE</td><td>olfactory epithelium</td></tr><tr><td>OECs</td><td>olfactory ensheathing cells</td></tr><tr><td>ONL</td><td>outer nerve layer</td></tr><tr><td>PNI</td><td>peripheral nerve injury</td></tr><tr><td>PNS</td><td>peripheral nervous system</td></tr><tr><td>PON</td><td>primary olfactory neuron</td></tr><tr><td>POS</td><td>primary olfactory system</td></tr><tr><td>RMS</td><td>repetitive magnetic stimulation</td></tr><tr><td>SCs</td><td>Schwann cells</td></tr><tr><td>SCI</td><td>spinal cord injury</td></tr><tr><td>SN</td><td>sciatic nerve</td></tr><tr><td>VMC</td><td>ventral mesencephalic cells</td></tr><tr><td>TBI</td><td>traumatic brain injury</td></tr><tr><td>TNF-α</td><td>tumor necrosis factors alpha</td></tr></table>
## References

1. Graziadei, P.P.C.; Graziadei, G.A.M. Neurogenesis and neuron regeneration in the olfactory system of mammals. I. Morphological aspects of differentiation and structural organization of the olfactory sensory neurons. *J. Neurocytol.* **1979**, *8*, 1-18. [CrossRef] [PubMed]

2. Doucette, J.R.; Kiernan, J.A.; Flumerfelt, B.A. The re-innervation of olfactory glomeruli following transection of primary olfactory axons in the central or peripheral nervous system. *J. Anat.* **1983**, *137*, 1-19. [PubMed]

3. Samanen, D.W.; Forbes, W.B. Replication and differentiation of olfactory receptor neurons following axotomy in the adult hamster: A morphometric analysis of postnatal neurogenesis. *J. Comp. Neurol.* **1984**, *225*, 201-211. [CrossRef] [PubMed]

4. Huard, J.M.; Youngentob, S.L.; Goldstein, B.J.; Luskin, M.B.; Schwob, J.E. Adult olfactory epithelium contains multipotent progenitors that give rise to neurons and non-neural cells. *J. Comp. Neurol.* **1998**, *400*, 469-486. [CrossRef]

5. Hadley, W.M.; Dahl, A.R. Cytochrome P-450 dependent monooxygenase activity in rat nasal epithelial membranes. *Toxicol. Lett.* **1982**, *10*, 417-422. [CrossRef]

6. Ressler, K.; Sullivan, S.L.; Buck, L.B. A molecular dissection of spatial patterning in the olfactory system. *Curr. Opin. Neurobiol.* **1994**, *4*, 588-596. [CrossRef]

7. Ressler, K.; Sullivan, S.L.; Buck, L.B. Information coding in the olfactory system: Evidence for a stereotyped and highly organized epitope map in the olfactory bulb. *Cell* **1994**, *79*, 1245-1255. [CrossRef]

8. Doucette, R. Glial influences on axonal growth in the primary olfactory system. *Glia* **1990**, *3*, 433-449. [CrossRef]

9. Chuah, M.I.; Au, C. Olfactory Schwann cells are derived from precursor cells in the olfactory epithelium. *J. Neurosci.* Res. **1991**, *29*, 172-180. [CrossRef]

10. Williams, S.K.; Franklin, R.J.; Barnett, S.C. Response of olfactory ensheathing cells to the degeneration and regeneration of the peripheral olfactory system and the involvement of the neuregulins. *J. Comp. Neurol.* **2004**, *470*, 50-62. [CrossRef]

11. Li, Y.; Field, P.M.; Raisman, G. Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres. *Glia* **2005**, *52*, 245-251. [CrossRef] [PubMed]

12. Forni, P.E.; Taylor-Burds, C.; Melvin, V.S.; Williams, T.; Wray, S.; Williams, T. Neural Crest and Ectodermal Cells Intermix in the Nasal Placode to Give Rise to GnRH-1 Neurons, Sensory Neurons, and Olfactory Ensheathing Cells. *J. Neurosci.* **2011**, *31*, 6915-6927. [CrossRef] [PubMed]

13. Barraud, P.; Seferiadis, A.A.; Tyson, L.D.; Zwart, M.F.; Szabo-Rogers, H.L.; Ruhrberg, C.; Liu, K.J.; Baker, C.V.H. Neural crest origin of olfactory ensheathing glia. *Proc. Natl. Acad. Sci. USA* **2010**, *107*, 21040-21045. [CrossRef] [PubMed]

14. Wewetzer, K.; Verdú, E.; Angelov, D.; Navarro, X.; Navarro, E.V. Olfactory ensheathing glia and Schwann cells: Two of a kind? *Cell Tissue Res.* **2002**, *309*, 337-345. [CrossRef]

15. Lakatos, A.; Franklin, R.J.; Barnett, S.C. Olfactory ensheathing cells and Schwann cells differ in their in vitro interactions with astrocytes. *Glia* **2000**, *32*, 214-225. [CrossRef]

16. Vincent, A.J.; Taylor, J.; Choi-Lundberg, D.; West, A.K.; Chuah, M.I. Genetic expression profile of olfactory ensheathing cells is distinct from that of Schwann cells and astrocytes. *Glia* **2005**, *51*, 132-147. [CrossRef]

17. Franssen, E.H.; De Bree, F.M.; Essing, A.H.; Ramon-Cueto, A.; Verhaagen, J. Comparative gene expression profiling of olfactory ensheathing glia and Schwann cells indicates distinct tissue repair characteristics of olfactory ensheathing glia. *Glia* **2008**, *56*, 1285-1298. [CrossRef]

18. Kueh, J.L.-L.; Raisman, G.; Li, Y.; Stevens, R.; Li, D. Comparison of bulbar and mucosal olfactory ensheathing cells using FACS and simultaneous antigenic bivariate cell cycle analysis. *Glia* **2011**, *59*, 1658-1671. [CrossRef]

19. Smith, K.E.; Whitcroft, K.; Law, S.; Andrews, P.; Choi, D.; Jagger, D.J. Olfactory ensheathing cells from the nasal mucosa and olfactory bulb have distinct membrane properties. *J. Neurosci.* Res. **2020**, *98*, 888-901. [CrossRef]

20. Guérout, N.; Derambure, C.; Drouot, L.; Bon-Mardion, N.; Duclos, C.; Boyer, O.; Marie, J.-P. Comparative gene expression profiling of olfactory ensheathing cells from olfactory bulb and olfactory mucosa. *Glia* **2010**, *58*, 1570-1580. [CrossRef]

21. Wang, L.-B.; Xia, H.-C.; Lan, Y.-X.; Yang, P.; Zeng, Z.; Yadav, N.; Zhang, L.-J. Gene and protein expression profiles of olfactory ensheathing cells from olfactory bulb versus olfactory mucosa. *Neural Regen. Res.* **2022**, *17*, 440-449. [CrossRef] [PubMed]

22. Rela, L.; Piantanida, A.P.; Bordey, A.; Greer, C.A. Voltage-dependent K+currents contribute to heterogeneity of olfactory ensheathing cells. *Glia* **2015**, *63*, 1646-1659. [CrossRef] [PubMed]

23. Rela, L.; Bordey, A.; Greer, C.A. Olfactory ensheathing cell membrane properties are shaped by connectivity. *Glia* **2010**, *58*, 665-678. [CrossRef] [PubMed]

24. Au, W.W.; Treloar, H.B.; Greer, C.A. Sublaminar organization of the mouse olfactory bulb nerve layer. *J. Comp. Neurol.* **2002**, *446*, 68-80. [CrossRef] [PubMed]

25. Windus, L.C.E.; Lineburg, K.E.; Scott, S.E.; Claxton, C.; Mackay-Sim, A.; Key, B.; John, J.A.S. Lamellipodia mediate the heterogeneity of central olfactory ensheathing cell interactions. *J. Exp.* **2010**, *67*, 1735-1750. [CrossRef] [PubMed]

26. Honoré, A.; Le Corre, S.; Derambure, C.; Normand, R.; Duclos, C.; Boyer, O.; Marie, J.-P.; Guérout, N. Isolation, characterization, and genetic profiling of subpopulations of olfactory ensheathing cells from the olfactory bulb. *Glia* **2012**, *60*, 404-413. [CrossRef] [PubMed]

27. Barber, P.; Lindsay, R. Schwann cells of the olfactory nerves contain glial fibrillary acidic protein and resemble astrocytes. *J. Neurosci.* **1982**, *7*, 3077-3090. [CrossRef]
References

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2. Doucette, J.R.; Kiernan, J.A.; Flumerfelt, B.A. The re-innervation of olfactory glomeruli following transection of primary olfactory axons in the central or peripheral nervous system. *J. Anat.* **1983**, *137*, 1–19. [PubMed]

3. Samanen, D.W.; Forbes, W.B. Replication and differentiation of olfactory receptor neurons following axotomy in the adult hamster: A morphometric analysis of postnatal neurogenesis. *J. Comp. Neurol.* **1984**, *225*, 201–211. [CrossRef] [PubMed]

4. Huard, J.M.; Youngentob, S.L.; Goldstein, B.J.; Luskin, M.B.; Schwob, J.E. Adult olfactory epithelium contains multipotent progenitors that give rise to neurons and non-neural cells. *J. Comp. Neurol.* **1998**, *400*, 469–486. [CrossRef]

5. Hadley, W.M.; Dahl, A.R. Cytochrome P-450 dependent monooxygenase activity in rat nasal epithelial membranes. *Toxicol. Lett.* **1982**, *10*, 417–422. [CrossRef]

6. Ressler, K.; Sullivan, S.L.; Buck, L.B. A molecular dissection of spatial patterning in the olfactory system. *Curr. Opin. Neurobiol.* **1994**, *4*, 588–596. [CrossRef]

7. Ressler, K.; Sullivan, S.L.; Buck, L.B. Information coding in the olfactory system: Evidence for a stereotyped and highly organized epitope map in the olfactory bulb. *Cell* **1994**, *79*, 1245–1255. [CrossRef]

8. Doucette, R. Glial influences on axonal growth in the primary olfactory system. *Glia* **1990**, *3*, 433–449. [CrossRef]

9. Chuah, M.I.; Au, C. Olfactory Schwann cells are derived from precursor cells in the olfactory epithelium. *J. Neurosci.* Res. **1991**, *29*, 172–180. [CrossRef]

10. Williams, S.K.; Franklin, R.J.; Barnett, S.C. Response of olfactory ensheathing cells to the degeneration and regeneration of the peripheral olfactory system and the involvement of the neuregulins. *J. Comp. Neurol.* **2004**, *470*, 50–62. [CrossRef]

11. Li, Y.; Field, P.M.; Raisman, G. Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres. *Glia* **2005**, *52*, 245–251. [CrossRef] [PubMed]

12. Forni, P.E.; Taylor-Burds, C.; Melvin, V.S.; Williams, T.; Wray, S.; Williams, T. Neural Crest and Ectodermal Cells Intermix in the Nasal Placode to Give Rise to GnRH-1 Neurons, Sensory Neurons, and Olfactory Ensheathing Cells. *J. Neurosci.* **2011**, *31*, 6915–6927. [CrossRef] [PubMed]

13. Barraud, P.; Seferiadis, A.A.; Tyson, L.D.; Zwart, M.F.; Szabo-Rogers, H.L.; Ruhrberg, C.; Liu, K.J.; Baker, C.V.H. Neural crest origin of olfactory ensheathing glia. *Proc. Natl. Acad. Sci. USA* **2010**, *107*, 21040–21045. [CrossRef] [PubMed]

14. Wewetzer, K.; Verdú, E.; Angelov, D.; Navarro, X.; Navarro, E.V. Olfactory ensheathing glia and Schwann cells: Two of a kind? *Cell Tissue Res.* **2002**, *309*, 337–345. [CrossRef]

15. Lakatos, A.; Franklin, R.J.; Barnett, S.C. Olfactory ensheathing cells and Schwann cells differ in their in vitro interactions with astrocytes. *Glia* **2000**, *32*, 214–225. [CrossRef]

16. Vincent, A.J.; Taylor, J.; Choi-Lundberg, D.; West, A.K.; Chuah, M.I. Genetic expression profile of olfactory ensheathing cells is distinct from that of Schwann cells and astrocytes. *Glia* **2005**, *51*, 132–147. [CrossRef]

17. Franssen, E.H.; De Bree, F.M.; Essing, A.H.; Ramon-Cueto, A.; Verhaagen, J. Comparative gene expression profiling of olfactory ensheathing glia and Schwann cells indicates distinct tissue repair characteristics of olfactory ensheathing glia. *Glia* **2008**, *56*, 1285–1298. [CrossRef]

18. Kueh, J.L.-L.; Raisman, G.; Li, Y.; Stevens, R.; Li, D. Comparison of bulbar and mucosal olfactory ensheathing cells using FACS and simultaneous antigenic bivariate cell cycle analysis. *Glia* **2011**, *59*, 1658–1671. [CrossRef]

19. Smith, K.E.; Whitcroft, K.; Law, S.; Andrews, P.; Choi, D.; Jagger, D.J. Olfactory ensheathing cells from the nasal mucosa and olfactory bulb have distinct membrane properties. *J. Neurosci.* Res. **2020**, *98*, 888–901. [CrossRef]

20. Guérout, N.; Derambure, C.; Drouot, L.; Bon-Mardion, N.; Duclos, C.; Boyer, O.; Marie, J.-P. Comparative gene expression profiling of olfactory ensheathing cells from olfactory bulb and olfactory mucosa. *Glia* **2010**, *58*, 1570–1580. [CrossRef]

21. Wang, L.-B.; Xia, H.-C.; Lan, Y.-X.; Yang, P.; Zeng, Z.; Yadav, N.; Zhang, L.-J. Gene and protein expression profiles of olfactory ensheathing cells from olfactory bulb versus olfactory mucosa. *Neural Regen. Res.* **2022**, *17*, 440–449. [CrossRef] [PubMed]

22. Rela, L.; Piantanida, A.P.; Bordey, A.; Greer, C.A. Voltage-dependent K+currents contribute to heterogeneity of olfactory ensheathing cells. *Glia* **2015**, *63*, 1646–1659. [CrossRef] [PubMed]

23. Rela, L.; Bordey, A.; Greer, C.A. Olfactory ensheathing cell membrane properties are shaped by connectivity. *Glia* **2010**, *58*, 665–678. [CrossRef] [PubMed]

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26. Honoré, A.; Le Corre, S.; Derambure, C.; Normand, R.; Duclos, C.; Boyer, O.; Marie, J.-P.; Guérout, N. Isolation, characterization, and genetic profiling of subpopulations of olfactory ensheathing cells from the olfactory bulb. *Glia* **2012**, *60*, 404–413. [CrossRef] [PubMed]

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30. Chuah, M.I.; Au, C. Olfactory cell cultures on ensheathing cell monolayers. *Chem. Senses* **1994**, *19*, 25–34. [CrossRef]

31. Gong, Q.; Bailey, M.S.; Pixley, S.K.; Ennis, M.; Liu, W.; Shipley, M.T. Localization and regulation of low affinity nerve growth factor receptor expression in the rat olfactory system during development and regeneration. *J. Comp. Neurol.* **1994**, *344*, 336–348.
[CrossRef] [PubMed]

32. Bailey, M.S.; Shipley, M.T. Astrocyte subtypes in the rat olfactory bulb: Morphological heterogeneity and differential laminar distribution. *J. Comp. Neurol.* **1993**, *328*, 501–526. [CrossRef] [PubMed]

33. Astic, L.; Pellier-Monnin, V.; Godinot, F. Spatio-temporal patterns of ensheathing cell differentiation in the rat olfactory system during development. *J. Neurosci.* **1998**, *84*, 295–307. [CrossRef]

34. Ubink, R.; Halasz, N.; Zhang, X.; Dagerlind, Å.; Hökfelt, T. Neuropeptide tyrosine is expressed in ensheathing cells around the olfactory nerves in the rat olfactory bulb. *J. Neurosci.* **1994**, *60*, 709–726. [CrossRef]

35. Barnett, S.C.; Hutchins, A.-M.; Noble, M. Purification of Olfactory Nerve Ensheathing Cells from the Olfactory Bulb. *Dev. Biol.* **1993**, *155*, 337–350. [CrossRef]

36. Ubink, R.; Hökfelt, T. Expression of neuropeptide Y in olfactory ensheathing cells during prenatal development. *J. Comp. Neurol.* **2000**, *423*, 13–25. [CrossRef]

37. Hisaoka, T.; Morikawa, Y.; Kitamura, T.; Senba, E. Expression of a member of tumor necrosis factor receptor superfamily, TROY, in the developing olfactory system. *Glia* **2004**, *45*, 313–324. [CrossRef]

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61. Feng, L.; Meng, H.; Wu, F.; Cheng, B.; He, X.; Wang, X.; Li, Z.; Liu, S. Olfactory ensheathing cells conditioned medium prevented apoptosis induced by 6-OHDA in PC12 cells through modulation of intrinsic apoptotic pathways. *Int. J. Dev. Neurosci.* **2008**, *26*, 323–329. [CrossRef] [PubMed]

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63. Debon, R.; Doucette, R. Olfactory ensheathing cells myelinate dorsal root ganglion neurites. *Brain Res.* **1992**, *589*, 175–179. [CrossRef]

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75. Hao, D.-J.; Liu, C.; Zhang, L.; Chen, B.; Zhang, Q.; Zhang, R.; Qian, Z.; Zhao, J.; Wu, M.; Wang, Y.; et al. Lipopolysaccharide and Curcumin Co-Stimulation Potentiates Olfactory Ensheathing Cell Phagocytosis Via Enhancing Their Activation. *J. Neurother.* **2017**, *14*, 502–518. [CrossRef] [PubMed]

76. He, B.-R.; Xie, S.-T.; Wu, M.-M.; Hao, D.-J.; Yang, H. Phagocytic Removal of Neuronal Debris by Olfactory Ensheathing Cells Enhances Neuronal Survival and Neurite Outgrowth via p38MAPK Activity. *Mol. Neurobiol.* **2014**, *49*, 1501–1512. [CrossRef] [PubMed]

77. Li, Y.; Zou, T.; Xue, L.; Yin, Z.Q.; Huo, S.; Xu, H. TGF-β1 enhances phagocytic removal of neuron debris and neuronal survival by olfactory ensheathing cells via integrin/MFG-E8 signaling pathway. *Mol. Cell. Neurosci.* **2017**, *85*, 45–56. [CrossRef]

78. Nazareth, L.; Lineburg, K.E.; Chuah, M.I.; Velasquez, J.T.; Chehrehasa, F.; John, J.S.; Ekberg, J.A. Olfactory ensheathing cells are the main phagocytic cells that remove axon debris during early development of the olfactory system. *J. Comp. Neurol.* **2015**, *523*, 479–494. [CrossRef]

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80. Su, Z.; Chen, J.; Qiu, Y.; Yuan, Y.; Zhu, F.; Zhu, Y.; Liu, X.; Pu, Y.; He, C. Olfactory ensheathing cells: The primary innate immunocytes in the olfactory pathway to engulf apoptotic olfactory nerve debris. *Glia* **2013**, *61*, 490–503. [CrossRef]

81. Velasquez, I.T.; Watts, M.E.; Todorovic, M.; Nazareth, L.; Pastrana, E.; Diaz, N.J.; Lim, F.; Ekberg, J.A.; Quinn, R.J.; John, J.A.S. Low-Dose Curcumin Stimulates Proliferation, Migration and Phagocytic Activity of Olfactory Ensheathing Cells. *PLoS ONE* **2014**, *9*, e111787. [CrossRef]
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58. Pellitteri, R.; Spatuzza, M.; Russo, A.; Zaccheo, D.; Stanzani, S. Olfactory ensheathing cells represent an optimal substrate for hippocampal neurons: An in vitro study. *Int. J. Dev. Neurosci.* **2009**, *27*, 453–458. [CrossRef]

59. Pellitteri, R.; Spatuzza, M.; Russo, A.; Stanzani, S. Olfactory ensheathing cells exert a trophic effect on the hypothalamic neurons in vitro. *Neurosci. Lett.* **2007**, *417*, 24–29. [CrossRef]

60. Doncel-Pérez, E.; Caballero-Chacón, S.; Nieto-Sampedro, M. Neurosphere cell differentiation to aldynoglia promoted by olfactory ensheathing cell conditioned medium. *Glia* **2009**, *57*, 1393–1409. [CrossRef]

61. Feng, L.; Meng, H.; Wu, F.; Cheng, B.; He, X.; Wang, X.; Li, Z.; Liu, S. Olfactory ensheathing cells conditioned medium prevented apoptosis induced by 6-OHDA in PC12 cells through modulation of intrinsic apoptotic pathways. *Int. J. Dev. Neurosci.* **2008**, *26*, 323–329. [CrossRef] [PubMed]

62. Runyan, S.A.; Phelps, P.E. Mouse olfactory ensheathing glia enhance axon outgrowth on a myelin substrate in vitro. *Exp. Neurol.* **2009**, *216*, 95–104. [CrossRef] [PubMed]

63. Debon, R.; Doucette, R. Olfactory ensheathing cells myelinate dorsal root ganglion neurites. *Brain Res.* **1992**, *589*, 175–179. [CrossRef]

64. Zhang, J.; Wang, B.; Xiao, Z.; Zhao, Y.; Chen, B.; Han, J.; Gao, Y.; Ding, W.; Zhang, H.; Dai, J. Olfactory ensheathing cells promote proliferation and inhibit neuronal differentiation of neural progenitor cells through activation of Notch signaling. *J. Neurosci.* **2008**, *153*, 406–413. [CrossRef] [PubMed]

65. Plant, G.W.; Currier, P.F.; Cuervo, E.P.; Bates, M.L.; Pressman, Y.; Bunge, M.B.; Wood, P.M. Purified Adult Ensheathing Glia Fail to Myelinate Axons under Culture Conditions that Enable Schwann Cells to Form Myelin. *J. Neurosci.* **2002**, *22*, 6083–6091. [CrossRef]

66. Franssen, E.H.P.; Roet, K.C.D.; de Bree, F.M.; Verhaagen, J. Olfactory ensheathing glia and Schwann cells exhibit a distinct interaction behavior with meningeal cells. *J. Neurosci. Res.* **2009**, *87*, 1556–1564. [CrossRef]

67. Carr, V.M.; Farbman, A.I. The Dynamics of Cell Death in the Olfactory Epithelium. *Exp. Neurol.* **1993**, *124*, 308–314. [CrossRef]

68. Chan, C.; Ekberg, J.A.; Lineburg, K.E.; Scott, S.E.; Chehrehasa, F.; Windus, L.C.; Claxton, C.; Mackay-Sim, A.; Key, B.; John, J.A.S. Correction of aberrant axon growth in the developing mouse olfactory bulb. *Mol. Cell. Neurosci.* **2011**, *46*, 282–295. [CrossRef]

69. Tenne-Brown, J.; Key, B. Errors in lamina growth of primary olfactory axons in the rat and mouse olfactory bulb. *J. Comp. Neurol.* **1999**, *410*, 20–30. [CrossRef]

70. Weiler, E.; Farbman, A.I. Proliferation in the Rat Olfactory Epithelium: Age-Dependent Changes. *J. Neurosci.* **1997**, *17*, 3610–3622. [CrossRef]

71. Weiler, E.; Farbman, A.I. Proliferation Decrease in the Olfactory Epithelium during Postnatal Development. *Ann. N. Y. Acad. Sci.* **1998**, *855*, 230–234. [CrossRef] [PubMed]

72. Calandra, T.; Roger, T. Macrophage migration inhibitory factor: A regulator of innate immunity. *Nat. Rev. Immunol.* **2003**, *3*, 791–800. [CrossRef] [PubMed]

73. Niino, M.; Ogata, A.; Kikuchi, S.; Tashiro, K.; Nishihira, J. Macrophage migration inhibitory factor in the cerebrospinal fluid of patients with conventional and optic-spinal forms of multiple sclerosis and neuro-Behçet's disease. *J. Neurol. Sci.* **2000**, *179*, 127–131. [CrossRef]

74. Wright, A.; Todorovic, M.; Murtaza, M.; John, J.S.; Ekberg, J. Macrophage migration inhibitory factor and its binding partner HTRA1 are expressed by olfactory ensheathing cells. *Mol. Cell. Neurosci.* **2020**, *102*, 103450. [CrossRef]

75. Hao, D.-J.; Liu, C.; Zhang, L.; Chen, B.; Zhang, Q.; Zhang, R.; Qian, Z.; Zhao, J.; Wu, M.; Wang, Y.; et al. Lipopolysaccharide and Curcumin Co-Stimulation Potentiates Olfactory Ensheathing Cell Phagocytosis Via Enhancing Their Activation. *J. Neurother.* **2017**, *14*, 502–518. [CrossRef] [PubMed]

76. He, B.-R.; Xie, S.-T.; Wu, M.-M.; Hao, D.-J.; Yang, H. Phagocytic Removal of Neuronal Debris by Olfactory Ensheathing Cells Enhances Neuronal Survival and Neurite Outgrowth via p38MAPK Activity. *Mol. Neurobiol.* **2014**, *49*, 1501–1512. [CrossRef] [PubMed]

77. Li, Y.; Zou, T.; Xue, L.; Yin, Z.Q.; Huo, S.; Xu, H. TGF-β1 enhances phagocytic removal of neuron debris and neuronal survival by olfactory ensheathing cells via integrin/MFG-E8 signaling pathway. *Mol. Cell. Neurosci.* **2017**, *85*, 45–56. [CrossRef]

78. Nazareth, L.; Lineburg, K.E.; Chuah, M.I.; Velasquez, J.T.; Chehrehasa, F.; John, J.S.; Ekberg, J.A. Olfactory ensheathing cells are the main phagocytic cells that remove axon debris during early development of the olfactory system. *J. Comp. Neurol.* **2015**, *523*, 479–494. [CrossRef]

79. Nazareth, L.; Shelper, T.B.; Chacko, A.; Basu, S.; Delbaz, A.; Lee, J.Y.P.; Chen, M.; John, J.A.S.; Ekberg, J.A.K. Key differences between olfactory ensheathing cells and Schwann cells regarding phagocytosis of necrotic cells: Implications for transplantation therapies. *Sci. Rep.* **2020**, *10*, 1–15. [CrossRef]

80. Su, Z.; Chen, J.; Qiu, Y.; Yuan, Y.; Zhu, F.; Zhu, Y.; Liu, X.; Pu, Y.; He, C. Olfactory ensheathing cells: The primary innate immunocytes in the olfactory pathway to engulf apoptotic olfactory nerve debris. *Glia* **2013**, *61*, 490–503. [CrossRef]

81. Velasquez, I.T.; Watts, M.E.; Todorovic, M.; Nazareth, L.; Pastrana, E.; Diaz, N.J.; Lim, F.; Ekberg, J.A.; Quinn, R.J.; John, J.A.S. Low-Dose Curcumin Stimulates Proliferation, Migration and Phagocytic Activity of Olfactory Ensheathing Cells. *PLoS ONE* **2014**, *9*, e111787. [CrossRef]
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85. Zhang, L.; Zhuang, X.; Kotitalo, P.; Keller, T.; Krzyczmonik, A.; Haaparanta-Solin, M.; Solin, O.; Forsback, S.; Grönroos, T.J.; Han, C.; et al. Intravenous transplantation of olfactory ensheathing cells reduces neuroinflammation after spinal cord injury via interleukin-1 receptor antagonist. *Theranostics* **2021**, *11*, 1147–1161. [CrossRef]

86. Leung, J.Y.K.; Chapman, J.A.; Harris, J.A.; Hale, D.; Chung, R.S.; West, A.K.; Chuah, M.I. Olfactory ensheathing cells are attracted to, and can endocytose, bacteria. *J. Exp. 2008*, *65*, 2732–2739. [CrossRef]

87. Su, Z.; Yuan, Y.; Chen, J.; Cao, L.; Zhu, Y.; Gao, L.; Qiu, Y.; He, C. Reactive Astrocytes in Glial Scar Attract Olfactory Ensheathing Cells Migration by Secreted TNF-α in Spinal Cord Lesion of Rat. *PLoS ONE* **2009**, *4*, e8141. [CrossRef]

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83. Macedo-Ramos, H.; Campos, F.S.; Carvalho, L.; Ramos, I.; Teixeira, L.M.; De Souza, W.; Cavalcante, L.A.; Baetas-Da-Cruz, W. Olfactory ensheathing cells as putative host cells for Streptococcus pneumoniae: Evidence of bacterial invasion via mannose receptor-mediated endocytosis. *Neurosci. Res.* **2011**, *69*, 308–313. [CrossRef] [PubMed]

84. Shi, K.; Tian, D.-C.; Li, Z.-G.; Ducruet, A.F.; Lawton, M.T.; Shi, F.-D. Global brain inflammation in stroke. *Lancet Neurol.* **2019**, *18*, 1058–1066. [CrossRef]

85. Zhang, L.; Zhuang, X.; Kotitalo, P.; Keller, T.; Krzyczmonik, A.; Haaparanta-Solin, M.; Solin, O.; Forsback, S.; Grönroos, T.J.; Han, C.; et al. Intravenous transplantation of olfactory ensheathing cells reduces neuroinflammation after spinal cord injury via interleukin-1 receptor antagonist. *Theranostics* **2021**, *11*, 1147–1161. [CrossRef]

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87. Su, Z.; Yuan, Y.; Chen, J.; Cao, L.; Zhu, Y.; Gao, L.; Qiu, Y.; He, C. Reactive Astrocytes in Glial Scar Attract Olfactory Ensheathing Cells Migration by Secreted TNF-α in Spinal Cord Lesion of Rat. *PLoS ONE* **2009**, *4*, e8141. [CrossRef]

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109. Li, Y.; Decherchi, P.; Raisman, G. Transplantation of Olfactory Ensheathing Cells into Spinal Cord Lesions Restores Breathing and Climbing. *J. Neurosci.* **2003**, *23*, 727–731. [CrossRef]

110. Plant, G.W.; Christensen, C.L.; Oudega, M.; Bunge, M.B. Delayed Transplantation of Olfactory Ensheathing Glia Promotes Sparing/Regeneration of Supraspinal Axons in the Contused Adult Rat Spinal Cord. *J. Neurotrauma* **2003**, *20*, 1–16. [CrossRef]

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112. He, X.-J.; Wang, G.-Y.; Cheng, Z.-J.; Yuan, P.-W.; Li, H.-P. Olfactory ensheathing cell transplantation alters the expression of chondroitin sulfate proteoglycans and promotes axonal regeneration after spinal cord injury. *Neural Regen. Res.* **2021**, *16*, 1638–1644. [CrossRef] [PubMed]

113. Takami, T.; Oudega, M.; Bates, M.L.; Wood, P.M.; Kleitman, N.; Bunge, M.B. Schwann Cell but Not Olfactory Ensheathing Glia Transplants Improve Hindlimb Locomotor Performance in the Moderately Contused Adult Rat Thoracic Spinal Cord. *J. Neurosci.* **2002**, *22*, 6670–6681. [CrossRef] [PubMed]

114. Pearse, D.D.; Sanchez, A.R.; Pereira, F.C.; Andrade, C.M.; Puzis, R.; Pressman, Y.; Golden, K.; Kitay, B.M.; Blits, B.; Wood, P.M.; et al. Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: Survival, migration, axon association, and functional recovery. *Glia* **2007**, *55*, 976–1000. [CrossRef]

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116. Mayeur, A.; Duclos, C.; Honoré, A.; Gauberti, M.; Drouot, L.; Rego, J.-C.D.; Bon-Mardion, N.; Jean, L.; Vérin, E.; Emery, E.; et al. Potential of Olfactory Ensheathing Cells from Different Sources for Spinal Cord Repair. *PLoS ONE* **2013**, *8*, e62860. [CrossRef]

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118. Lopez-Vales, R.; Forés, J.; Navarro, X.; Verdú, E. Chronic transplantation of olfactory ensheathing cells promotes partial recovery after complete spinal cord transection in the rat. *Glia* **2007**, *55*, 303–311. [CrossRef] [PubMed]

119. Stamegna, J.; Felix, M.; Roux-Peyronnet, J.; Rossi, V.; Féron, F.; Gauthier, P.; Matarazzo, V. Nasal OEC transplantation promotes respiratory recovery in a subchronic rat model of cervical spinal cord contusion. *Exp. Neurol.* **2011**, *229*, 120–131. [CrossRef]

120. Watzlawick, R.; Rind, J.; Sena, E.S.; Brommer, B.; Zhang, T.; Kopp, M.A.; Dirnagl, U.; MacLeod, M.R.; Howells, D.W.; Schwab, J.M. Olfactory Ensheathing Cell Transplantation in Experimental Spinal Cord Injury: Effect size and Reporting Bias of 62 Experimental Treatments: A Systematic Review and Meta-Analysis. *PLoS Biol.* **2016**, *14*, e1002468. [CrossRef]

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123. Lu, J.; Ashwell, K. Olfactory Ensheathing Cells. *Spine* **2002**, *27*, 887–892. [CrossRef]

124. Franssen, E.H.; de Bree, F.M.; Verhaagen, J. Olfactory ensheathing glia: Their contribution to primary olfactory nervous system regeneration and their regenerative potential following transplantation into the injured spinal cord. *Brain Res. Rev.* **2007**, *56*, 236–258. [CrossRef] [PubMed]

125. O'Toole, D.A.; West, A.K.; Chuah, M.I. Effect of olfactory ensheathing cells on reactive astrocytes in vitro. *Cell. Mol. Life Sci.* **2007**, *64*, 1303–1309. [CrossRef] [PubMed]

126. Li, B.C.; Li, Y.; Chen, L.F.; Chang, J.Y.; Duan, Z.X. Olfactory ensheathing cells can reduce the tissue loss but not the cavity formation in contused spinal cord of rats. *J. Neurol. Sci.* **2011**, *303*, 67–74. [CrossRef] [PubMed]

127. Zhang, S.-X.; Huang, F.; Gates, M.; Holmberg, E.G. Scar ablation combined with LP/OEC transplantation promotes anatomical recovery and P0-positive myelination in chronically contused spinal cord of rats. *Brain Res.* **2011**, *1399*, 1–14. [CrossRef]

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129. Assinck, P.; Duncan, G.J.; Plemel, J.R.; Lee, M.; Stratton, J.A.; Manesh, S.B.; Liu, J.; Ramer, L.M.; Kang, S.H.; Bergles, D.E.; et al. Myelinogenic Plasticity of Oligodendrocyte Precursor Cells following Spinal Cord Contusion Injury. *J. Neurosci.* **2017**, *37*, 8635–8654. [CrossRef]

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107. Gilmour, A.; Reshamwala, R.; Wright, A.A.; Ekberg, J.A.; John, J.A.S. Optimizing Olfactory Ensheathing Cell Transplantation for Spinal Cord Injury Repair. *J. Neurotrauma* **2020**, *37*, 817–829. [CrossRef] [PubMed]

108. Ramón-Cueto, A.; Cordero, M.I.; Santos-Benito, F.F.; Avila, J. Functional Recovery of Paraplegic Rats and Motor Axon Regeneration in Their Spinal Cords by Olfactory Ensheathing Glia. *Neuron* **2000**, *25*, 425–435. [CrossRef]

109. Li, Y.; Decherchi, P.; Raisman, G. Transplantation of Olfactory Ensheathing Cells into Spinal Cord Lesions Restores Breathing and Climbing. *J. Neurosci.* **2003**, *23*, 727–731. [CrossRef]

110. Plant, G.W.; Christensen, C.L.; Oudega, M.; Bunge, M.B. Delayed Transplantation of Olfactory Ensheathing Glia Promotes Sparing/Regeneration of Supraspinal Axons in the Contused Adult Rat Spinal Cord. *J. Neurotrauma* **2003**, *20*, 1–16. [CrossRef]

111. Keyvan-Fouladi, N.; Raisman, G.; Li, Y. Functional Repair of the Corticospinal Tract by Delayed Transplantation of Olfactory Ensheathing Cells in Adult Rats. *J. Neurosci.* **2003**, *23*, 9428–9434. [CrossRef] [PubMed]

112. He, X.-J.; Wang, G.-Y.; Cheng, Z.-J.; Yuan, P.-W.; Li, H.-P. Olfactory ensheathing cell transplantation alters the expression of chondroitin sulfate proteoglycans and promotes axonal regeneration after spinal cord injury. *Neural Regen. Res.* **2021**, *16*, 1638–1644. [CrossRef] [PubMed]

113. Takami, T.; Oudega, M.; Bates, M.L.; Wood, P.M.; Kleitman, N.; Bunge, M.B. Schwann Cell but Not Olfactory Ensheathing Glia Transplants Improve Hindlimb Locomotor Performance in the Moderately Contused Adult Rat Thoracic Spinal Cord. *J. Neurosci.* **2002**, *22*, 6670–6681. [CrossRef] [PubMed]

114. Pearse, D.D.; Sanchez, A.R.; Pereira, F.C.; Andrade, C.M.; Puzis, R.; Pressman, Y.; Golden, K.; Kitay, B.M.; Blits, B.; Wood, P.M.; et al. Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: Survival, migration, axon association, and functional recovery. *Glia* **2007**, *55*, 976–1000. [CrossRef]

115. Nategh, M.; Firouzi, M.; Naji-Tehrani, M.; Zanjani, L.O.; Hassannejad, Z.; Nabian, M.H.; Zadegan, S.; Karimi, M.; Rahimi-Movaghar, V. Subarachnoid Space Transplantation of Schwann and/or Olfactory Ensheathing Cells Following Severe Spinal Cord Injury Fails to Improve Locomotor Recovery in Rats. *Acta Med. Iran.* **2016**, *54*, 562–569. [PubMed]

116. Mayeur, A.; Duclos, C.; Honoré, A.; Gauberti, M.; Drouot, L.; Rego, J.-C.D.; Bon-Mardion, N.; Jean, L.; Vérin, E.; Emery, E.; et al. Potential of Olfactory Ensheathing Cells from Different Sources for Spinal Cord Repair. *PLoS ONE* **2013**, *8*, e62860. [CrossRef]

117. Khankan, R.R.; Griffis, K.G.; Haggerty-Skeans, J.R.; Zhong, H.; Roy, R.R.; Edgerton, V.R.; Phelps, P.E. Olfactory Ensheathing Cell Transplantation after a Complete Spinal Cord Transection Mediates Neuroprotective and Immunomodulatory Mechanisms to Facilitate Regeneration. *J. Neurosci.* **2016**, *36*, 6269–6286. [CrossRef] [PubMed]

118. Lopez-Vales, R.; Forés, J.; Navarro, X.; Verdú, E. Chronic transplantation of olfactory ensheathing cells promotes partial recovery after complete spinal cord transection in the rat. *Glia* **2007**, *55*, 303–311. [CrossRef] [PubMed]

119. Stamegna, J.; Felix, M.; Roux-Peyronnet, J.; Rossi, V.; Féron, F.; Gauthier, P.; Matarazzo, V. Nasal OEC transplantation promotes respiratory recovery in a subchronic rat model of cervical spinal cord contusion. *Exp. Neurol.* **2011**, *229*, 120–131. [CrossRef]

120. Watzlawick, R.; Rind, J.; Sena, E.S.; Brommer, B.; Zhang, T.; Kopp, M.A.; Dirnagl, U.; MacLeod, M.R.; Howells, D.W.; Schwab, J.M. Olfactory Ensheathing Cell Transplantation in Experimental Spinal Cord Injury: Effect size and Reporting Bias of 62 Experimental Treatments: A Systematic Review and Meta-Analysis. *PLoS Biol.* **2016**, *14*, e1002468. [CrossRef]

121. Nakhjavan-Shahraki, B.; Yousefifard, M.; Rahimi-Movaghar, V.; Baikpour, M.; Nasirinezhad, F.; Safari, S.; Yaseri, M.; Jafari, A.M.; Ghelichkhani, P.; Tafakhori, A.; et al. Transplantation of olfactory ensheathing cells on functional recovery and neuropathic pain after spinal cord injury; systematic review and meta-analysis. *Sci. Rep.* **2018**, *8*, 325. [CrossRef] [PubMed]

122. Delarue, Q.; Mayeur, A.; Chalfouh, C.; Honoré, A.; Duclos, C.; Di Giovanni, M.; Li, X.; Salaun, M.; Dampierre, J.; Vaudry, D.; et al. Inhibition of ADAMTS-4 Expression in Olfactory Ensheathing Cells Enhances Recovery after Transplantation within Spinal Cord Injury. *J. Neurotrauma* **2020**, *37*, 507–516. [CrossRef] [PubMed]

123. Lu, J.; Ashwell, K. Olfactory Ensheathing Cells. *Spine* **2002**, *27*, 887–892. [CrossRef]

124. Franssen, E.H.; de Bree, F.M.; Verhaagen, J. Olfactory ensheathing glia: Their contribution to primary olfactory nervous system regeneration and their regenerative potential following transplantation into the injured spinal cord. *Brain Res. Rev.* **2007**, *56*, 236–258. [CrossRef] [PubMed]

125. O'Toole, D.A.; West, A.K.; Chuah, M.I. Effect of olfactory ensheathing cells on reactive astrocytes in vitro. *Cell. Mol. Life Sci.* **2007**, *64*, 1303–1309. [CrossRef] [PubMed]

126. Li, B.C.; Li, Y.; Chen, L.F.; Chang, J.Y.; Duan, Z.X. Olfactory ensheathing cells can reduce the tissue loss but not the cavity formation in contused spinal cord of rats. *J. Neurol. Sci.* **2011**, *303*, 67–74. [CrossRef] [PubMed]

127. Zhang, S.-X.; Huang, F.; Gates, M.; Holmberg, E.G. Scar ablation combined with LP/OEC transplantation promotes anatomical recovery and P0-positive myelination in chronically contused spinal cord of rats. *Brain Res.* **2011**, *1399*, 1–14. [CrossRef]

128. Zhang, S.-X.; Huang, F.; Gates, M.; Holmberg, E.G. Role of endogenous Schwann cells in tissue repair after spinal cord injury. *Neural Regen. Res.* **2013**, *8*, 177–185. [CrossRef]

129. Assinck, P.; Duncan, G.J.; Plemel, J.R.; Lee, M.; Stratton, J.A.; Manesh, S.B.; Liu, J.; Ramer, L.M.; Kang, S.H.; Bergles, D.E.; et al. Myelinogenic Plasticity of Oligodendrocyte Precursor Cells following Spinal Cord Contusion Injury. *J. Neurosci.* **2017**, *37*, 8635–8654. [CrossRef]

130. Li, Y.; Li, D.; Raisman, G. Interaction of olfactory ensheathing cells with astrocytes may be the key to repair of tract injuries in the spinal cord: The 'pathway hypothesis'. *J. Neurocytol.* **2005**, *34*, 343–351. [CrossRef]
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132. Imaizumi, T.; Lankford, K.L.; Waxman, S.G.; Greer, C.A.; Kocsis, J.D. Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. *J. Neurosci.* **1998**, *18*, 6176–6185. [CrossRef] [PubMed]

133. García-Alías, G.; Lopez-Vales, R.; Forés, J.; Navarro, X.; Verdú, E. Acute transplantation of olfactory ensheathing cells or Schwann cells promotes recovery after spinal cord injury in the rat. *J. Neurosci. Res.* **2004**, *75*, 632–641. [CrossRef]

134. Lankford, K.L.; Sasaki, M.; Radtke, C.; Kocsis, J.D. Olfactory ensheathing cells exhibit unique migratory, phagocytic, and myelinating properties in the X-irradiated spinal cord not shared by Schwann cells. *Glia* **2008**, *56*, 1664–1678. [CrossRef]

135. Sasaki, M.; Black, J.A.; Lankford, K.L.; Tokuno, H.A.; Waxman, S.G.; Kocsis, J.D. Molecular Reconstruction of Nodes of Ranvier after Remyelination by Transplanted Olfactory Ensheathing Cells in the Demyelinated Spinal Cord. *J. Neurosci.* **2006**, *26*, 1803–1812. [CrossRef] [PubMed]

136. Lankford, K.L.; Brown, R.J.; Sasaki, M.; Kocsis, J.D. Olfactory ensheathing cells, but not schwann cells, proliferate and migrate extensively within moderately X-Irradiated juvenile rat brain. *Glia* **2014**, *62*, 52–63. [CrossRef]

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138. Penna, V.; Stark, G.-B.; Wewetzer, K.; Radtke, C.; Lang, E.M. Comparison of Schwann Cells and Olfactory Ensheathing Cells for Peripheral Nerve Gap Bridging. *Cells Tissues Organs* **2012**, *196*, 534–542. [CrossRef]

139. Zhang, L.; Li, B.; Liu, B.; Dong, Z. Co-transplantation of Epidermal Neural Crest Stem Cells and Olfactory Ensheathing Cells Repairs Sciatic Nerve Defects in Rats. *Front. Cell. Neurosci.* **2019**, *13*, 253. [CrossRef]

140. Lee, J.-Y.; Kim, Y.-H.; Kim, B.-Y.; Jang, D.-H.; Choi, S.-W.; Joen, S.-H.; Kim, H.; Lee, S.-U. Peripheral Nerve Regeneration Using a Nerve Conduit with Olfactory Ensheathing Cells in a Rat Model. *Tissue Eng. Regen. Med.* **2021**, *18*, 453–465. [CrossRef]

141. Goulart, C.O.; Durço, D.F.P.A.; de Carvalho, L.A.; Oliveira, J.T.; Alves, L.; Cavalcante, L.A.; Martinez, A.M.B. Olfactory ensheathing glia cell therapy and tubular conduit enhance nerve regeneration after mouse sciatic nerve transection. *Brain Res.* **2016**, *1650*, 243–251. [CrossRef] [PubMed]

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143. Dombrowski, M.A.; Sasaki, M.; Lankford, K.L.; Kocsis, J.D.; Radtke, C. Myelination and nodal formation of regenerated peripheral nerve fibers following transplantation of acutely prepared olfactory ensheathing cells. *Brain Res.* **2006**, *1125*, 1–8. [CrossRef] [PubMed]

144. Guntinas-Lichius, O.; Wewetzer, K.; Tomov, T.L.; Azzolin, N.; Kazemi, S.; Streppel, M.; Neiss, W.F.; Angelov, D.N. Transplantation of Olfactory Mucosa Minimizes Axonal Branching and Promotes the Recovery of Vibrissae Motor Performance after Facial Nerve Repair in Rats. *J. Neurosci.* **2002**, *22*, 7121–7131. [CrossRef] [PubMed]

145. Guntinas-Lichius, O.; Angelov, D.N.; Tomov, T.L.; Dramiga, J.; Neiss, W.F.; Wewetzer, K. Transplantation of Olfactory Ensheathing Cells Stimulates the Collateral Sprouting from Axotomized Adult Rat Facial Motoneurons. *Exp. Neurol.* **2001**, *172*, 70–80. [CrossRef]

146. Li, Y.; Sauvé, Y.; Li, D.; Lund, R.D.; Raisman, G. Transplanted Olfactory Ensheathing Cells Promote Regeneration of Cut Adult Rat Optic Nerve Axons. *J. Neurosci.* **2003**, *23*, 7783–7788. [CrossRef]

147. Li, Y.; Li, D.; Raisman, G. Transplanted Schwann cells, not olfactory ensheathing cells, myelinate optic nerve fibres. *Glia* **2007**, *55*, 312–316. [CrossRef]

148. Paviot, A.; Guérout, N.; Bon-Mardion, N.; Duclos, C.; Jean, L.; Boyer, O.; Marie, J.-P. Efficiency of laryngeal motor nerve repair is greater with bulbar than with mucosal olfactory ensheathing cells. *Neurobiol. Dis.* **2011**, *41*, 688–694. [CrossRef]

149. Guérout, N.; Paviot, A.; Bon-Mardion, N.; Duclos, C.; Genty, D.; Jean, L.; Boyer, O.; Marie, J.-P. Co-Transplantation of Olfactory Ensheathing Cells from Mucosa and Bulb Origin Enhances Functional Recovery after Peripheral Nerve Lesion. *PLoS ONE* **2011**, *6*, e22816. [CrossRef]

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151. Dewar, D.; Bentley, D.; Barnett, S.C. Implantation of pure cultured olfactory ensheathing cells in an animal model of parkinsonism. *Acta Neurochir.* **2007**, *149*, 407–414. [CrossRef] [PubMed]

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153. Liu, W.; Zheng, Q.; Wang, Y.; Han, X.; Yuan, L.; Zhao, M. Transplantation of Olfactory Ensheathing Cells Attenuates Acute Carbon Monoxide Poisoning-Induced Brain Damages in Rats. *Neurochem. Res.* **2015**, *40*, 70–80. [CrossRef] [PubMed]
131. Nazareth, L.; Velasquez, J.T.; Lineburg, K.E.; Chehrehasa, F.; John, J.A.S.; Ekberg, J.A. Differing phagocytic capacities of accessory and main olfactory ensheathing cells and the implication for olfactory glia transplantation therapies. *Mol. Cell. Neurosci.* **2015**, *65*, 92–101. [CrossRef] [PubMed]

132. Imaizumi, T.; Lankford, K.L.; Waxman, S.G.; Greer, C.A.; Kocsis, J.D. Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. *J. Neurosci.* **1998**, *18*, 6176–6185. [CrossRef] [PubMed]

133. García-Alías, G.; Lopez-Vales, R.; Forés, J.; Navarro, X.; Verdú, E. Acute transplantation of olfactory ensheathing cells or Schwann cells promotes recovery after spinal cord injury in the rat. *J. Neurosci. Res.* **2004**, *75*, 632–641. [CrossRef]

134. Lankford, K.L.; Sasaki, M.; Radtke, C.; Kocsis, J.D. Olfactory ensheathing cells exhibit unique migratory, phagocytic, and myelinating properties in the X-irradiated spinal cord not shared by Schwann cells. *Glia* **2008**, *56*, 1664–1678. [CrossRef]

135. Sasaki, M.; Black, J.A.; Lankford, K.L.; Tokuno, H.A.; Waxman, S.G.; Kocsis, J.D. Molecular Reconstruction of Nodes of Ranvier after Remyelination by Transplanted Olfactory Ensheathing Cells in the Demyelinated Spinal Cord. *J. Neurosci.* **2006**, *26*, 1803–1812. [CrossRef] [PubMed]

136. Lankford, K.L.; Brown, R.J.; Sasaki, M.; Kocsis, J.D. Olfactory ensheathing cells, but not schwann cells, proliferate and migrate extensively within moderately X-Irradiated juvenile rat brain. *Glia* **2014**, *62*, 52–63. [CrossRef]

137. Guérout, N.; Duclos, C.; Drouot, L.; Abramovici, O.; Bon-Mardion, N.; Lacoume, Y.; Jean, L.; Boyer, O.; Marie, J.-P.; Marie, J. Transplantation of olfactory ensheathing cells promotes axonal regeneration and functional recovery of peripheral nerve lesion in rats. *Muscle Nerve* **2011**, *43*, 543–551. [CrossRef]

138. Penna, V.; Stark, G.-B.; Wewetzer, K.; Radtke, C.; Lang, E.M. Comparison of Schwann Cells and Olfactory Ensheathing Cells for Peripheral Nerve Gap Bridging. *Cells Tissues Organs* **2012**, *196*, 534–542. [CrossRef]

139. Zhang, L.; Li, B.; Liu, B.; Dong, Z. Co-transplantation of Epidermal Neural Crest Stem Cells and Olfactory Ensheathing Cells Repairs Sciatic Nerve Defects in Rats. *Front. Cell. Neurosci.* **2019**, *13*, 253. [CrossRef]

140. Lee, J.-Y.; Kim, Y.-H.; Kim, B.-Y.; Jang, D.-H.; Choi, S.-W.; Joen, S.-H.; Kim, H.; Lee, S.-U. Peripheral Nerve Regeneration Using a Nerve Conduit with Olfactory Ensheathing Cells in a Rat Model. *Tissue Eng. Regen. Med.* **2021**, *18*, 453–465. [CrossRef]

141. Goulart, C.O.; Durço, D.F.P.A.; de Carvalho, L.A.; Oliveira, J.T.; Alves, L.; Cavalcante, L.A.; Martinez, A.M.B. Olfactory ensheathing glia cell therapy and tubular conduit enhance nerve regeneration after mouse sciatic nerve transection. *Brain Res.* **2016**, *1650*, 243–251. [CrossRef] [PubMed]

142. You, H.; Wei, L.; Liu, Y.; Oudega, M.; Jiao, S.-S.; Feng, S.-N.; Chen, Y.; Chen, J.-M.; Li, B.-C. Olfactory ensheathing cells enhance Schwann cell-mediated anatomical and functional repair after sciatic nerve injury in adult rats. *Exp. Neurol.* **2011**, *229*, 158–167. [CrossRef] [PubMed]

143. Dombrowski, M.A.; Sasaki, M.; Lankford, K.L.; Kocsis, J.D.; Radtke, C. Myelination and nodal formation of regenerated peripheral nerve fibers following transplantation of acutely prepared olfactory ensheathing cells. *Brain Res.* **2006**, *1125*, 1–8. [CrossRef] [PubMed]

144. Guntinas-Lichius, O.; Wewetzer, K.; Tomov, T.L.; Azzolin, N.; Kazemi, S.; Streppel, M.; Neiss, W.F.; Angelov, D.N. Transplantation of Olfactory Mucosa Minimizes Axonal Branching and Promotes the Recovery of Vibrissae Motor Performance after Facial Nerve Repair in Rats. *J. Neurosci.* **2002**, *22*, 7121–7131. [CrossRef] [PubMed]

145. Guntinas-Lichius, O.; Angelov, D.N.; Tomov, T.L.; Dramiga, J.; Neiss, W.F.; Wewetzer, K. Transplantation of Olfactory Ensheathing Cells Stimulates the Collateral Sprouting from Axotomized Adult Rat Facial Motoneurons. *Exp. Neurol.* **2001**, *172*, 70–80. [CrossRef]

146. Li, Y.; Sauvé, Y.; Li, D.; Lund, R.D.; Raisman, G. Transplanted Olfactory Ensheathing Cells Promote Regeneration of Cut Adult Rat Optic Nerve Axons. *J. Neurosci.* **2003**, *23*, 7783–7788. [CrossRef]

147. Li, Y.; Li, D.; Raisman, G. Transplanted Schwann cells, not olfactory ensheathing cells, myelinate optic nerve fibres. *Glia* **2007**, *55*, 312–316. [CrossRef]

148. Paviot, A.; Guérout, N.; Bon-Mardion, N.; Duclos, C.; Jean, L.; Boyer, O.; Marie, J.-P. Efficiency of laryngeal motor nerve repair is greater with bulbar than with mucosal olfactory ensheathing cells. *Neurobiol. Dis.* **2011**, *41*, 688–694. [CrossRef]

149. Guérout, N.; Paviot, A.; Bon-Mardion, N.; Duclos, C.; Genty, D.; Jean, L.; Boyer, O.; Marie, J.-P. Co-Transplantation of Olfactory Ensheathing Cells from Mucosa and Bulb Origin Enhances Functional Recovery after Peripheral Nerve Lesion. *PLoS ONE* **2011**, *6*, e22816. [CrossRef]

150. Radtke, C.; Kocsis, J.D. Olfactory-Ensheathing Cell Transplantation for Peripheral Nerve Repair: Update on Recent Developments. *Cells Tissues Organs* **2015**, *200*, 48–58. [CrossRef]

151. Dewar, D.; Bentley, D.; Barnett, S.C. Implantation of pure cultured olfactory ensheathing cells in an animal model of parkinsonism. *Acta Neurochir.* **2007**, *149*, 407–414. [CrossRef] [PubMed]

152. Weng, S.-J.; Li, I.-H.; Huang, Y.-S.; Chueh, S.-H.; Chou, T.-K.; Huang, S.-Y.; Shiue, C.-Y.; Cheng, C.-Y.; Ma, K.-H. KA-bridged transplantation of mesencephalic tissue and olfactory ensheathing cells in a Parkinsonian rat model. *J. Tissue Eng. Regen. Med.* **2015**, *11*, 2024–2033. [CrossRef] [PubMed]

153. Liu, W.; Zheng, Q.; Wang, Y.; Han, X.; Yuan, L.; Zhao, M. Transplantation of Olfactory Ensheathing Cells Attenuates Acute Carbon Monoxide Poisoning-Induced Brain Damages in Rats. *Neurochem. Res.* **2015**, *40*, 70–80. [CrossRef] [PubMed]
154. Srivastava, N.; Seth, K.; Khanna, V.; Ansari, R.; Agrawal, A. Long-term functional restoration by neural progenitor cell transplantation in rat model of cognitive dysfunction: Co-transplantation with olfactory ensheathing cells for neurotrophic factor support. *Int. J. Dev. Neurosci.* **2009**, *27*, 103–110. [CrossRef] [PubMed]

155. Wang, Y.-C.; Xia, Q.-J.; Ba, Y.-C.; Wang, T.-Y.; Lin, N.; Zou, Y.; Shang, F.-F.; Zhou, X.-F.; Wang, T.-H.; Fu, X.-M.; et al. Transplantation of olfactory ensheathing cells promotes the recovery of neurological functions in rats with traumatic brain injury associated with downregulation of Bad. *Cytotherapy* **2014**, *16*, 1000–1010. [CrossRef] [PubMed]

156. Fu, X.-M.; Liu, S.-J.; Dan, Q.-Q.; Wang, Y.-P.; Lin, N.; Lv, L.-Y.; Zou, Y.; Zhou, X.; Wang, T.-H. Combined Bone Mesenchymal Stem Cell and Olfactory Ensheathing Cell Transplantation Promotes Neural Repair Associated with CNTF Expression in Traumatic Brain-Injured Rats. *Cell Transplant.* **2015**, *24*, 1533–1544. [CrossRef] [PubMed]

157. Liu, S.-J.; Zou, Y.; Belegu, V.; Lv, L.-Y.; Lin, N.; Wang, T.-Y.; McDonald, J.W.; Zhou, X.; Xia, Q.-J. Co-grafting of neural stem cells with olfactory en sheathing cells promotes neuronal restoration in traumatic brain injury with an anti-inflammatory mechanism. *J. Neuroinflammation* **2014**, *11*, 66. [CrossRef]

158. Zhai, W.; Gao, L.; Qu, L.; Li, Y.; Zeng, Y.; Li, Q.; Xu, H.; Yin, Z.Q. Combined Transplantation of Olfactory Ensheathing Cells with Rat Neural Stem Cells Enhanced the Therapeutic Effect in the Retina of RCS Rats. *Front. Cell. Neurosci.* **2020**, *14*, 52. [CrossRef]

159. Shi, X.; Kang, Y.; Hu, Q.; Chen, C.; Yang, L.; Wang, K.; Chen, L.; Huang, H.; Zhou, C. A long-term observation of olfactory ensheathing cells transplantation to repair white matter and functional recovery in a focal ischemia model in rat. *Brain Res.* **2010**, *1317*, 257–267. [CrossRef]

160. Tang, Z.-P.; Xie, X.-W.; Shi, Y.-H.; Liu, N.; Zhu, S.-Q.; Li, Z.-W.; Chen, Y. Combined Transplantation of Neural Stem Cells and Olfactory Ensheathing Cells Improves the Motor Function of Rats with Intracerebral Hemorrhage. *Biomed. Environ. Sci.* **2010**, *23*, 62–67. [CrossRef]

161. Carvalho, L.; Teng, J.; Fleming, R.L.; Tabet, E.; Zinter, M.; Reis, R.A.D.M.; Tannous, B. Olfactory Ensheathing Cells: A Trojan Horse for Glioma Gene Therapy. *JNCI J. Natl. Cancer Inst.* **2019**, *111*, 283–291. [CrossRef] [PubMed]

162. Chen, L.; Huang, H.; Zhang, J.; Zhang, F.; Liu, Y.; Xi, H.; Wang, H.; Gu, Z.; Song, Y.; Li, Y.; et al. Short-term outcome of olfactory ensheathing cells transplantation for treatment of amyotrophic lateral sclerosis. *Chin. J. Reparative Reconstr. Surg.* **2007**, *21*, 961–966.

163. Huang, H.; Chen, L.; Xi, H.; Wang, H.; Zhang, J.; Zhang, F.; Liu, Y. Fetal olfactory ensheathing cells transplantation in amyotrophic lateral sclerosis patients: A controlled pilot study. *Clin. Transplant.* **2008**, *22*, 710–718. [CrossRef] [PubMed]

164. Morita, E.; Watanabe, Y.; Ishimoto, M.; Nakano, T.; Kitayama, M.; Yasui, K.; Fukada, Y.; Doi, K.; Karunaratne, A.; Murrell, W.G.; et al. A novel cell transplantation protocol and its application to an ALS mouse model. *Exp. Neurol.* **2008**, *213*, 431–438. [CrossRef] [PubMed]

165. Giordana, M.T.; Grifoni, S.; Votta, B.; Magistrello, M.; Vercellino, M.; Pellerino, A.; Navone, R.; Valentini, C.; Calvo, A.; Chio, A. Neuropathology of Olfactory Ensheathing Cell Transplantation into the Brain of Two Amyotrophic Lateral Sclerosis (ALS) Patients. *Brain Pathol.* **2009**, *20*, 730–737. [CrossRef]

166. Piepers, S.; Berg, L.H.V.D. No benefits from experimental treatment with olfactory ensheathing cells in patients with ALS. *Amyotroph. Lateral Scler.* **2009**, *11*, 328–330. [CrossRef]

167. Chen, L.; Huang, H.; Xi, H.; Xie, Z.; Liu, R.; Jiang, Z.; Zhang, F.; Liu, Y.; Chen, D.; Wang, Q.; et al. Intracranial Transplant of Olfactory Ensheathing Cells in Children and Adolescents with Cerebral Palsy: A Randomized Controlled Clinical Trial. *Cell Transplant.* **2010**, *19*, 185–192. [CrossRef]

168. Ruitenberg, M.; Plant, G.W.; Christensen, C.L.; Blits, B.; Niclou, S.; Harvey, A.R.; Boer, G.J.; Verhaagen, J. Viral vector-mediated gene expression in olfactory ensheathing glia implants in the lesioned rat spinal cord. *Gene Ther.* **2002**, *9*, 135–146. [CrossRef]

169. Cao, L.; Liu, L.; Chen, Z.; Wang, L.; Ye, J.; Qiu, H.; Lu, C.; He, C. Olfactory ensheathing cells genetically modified to secrete GDNF to promote spinal cord repair. *Brain* **2003**, *127*, 535–549. [CrossRef]

170. Ma, Y.-H.; Zhang, Y.; Cao, L.; Su, J.-C.; Wang, Z.-W.; Xu, A.-B.; Zhang, S.-C. Effect of Neurotrophin-3 Genetically Modified Olfactory Ensheathing Cells Transplantation on Spinal Cord Injury. *Cell Transplant.* **2010**, *19*, 167–178. [CrossRef]

171. Carwardine, D.; Wong, L.-F.; Fawcett, J.W.; Muir, E.M.; Granger, N. Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC. *J. Neurol. Sci.* **2016**, *367*, 311–318. [CrossRef] [PubMed]

172. Johansson, S.; Lee, I.-H.; Olson, L.; Spenger, C. Olfactory ensheathing glial co-grafts improve functional recovery in rats with 6-OHDA lesions. *Brain* **2005**, *128*, 2961–2976. [CrossRef] [PubMed]

173. Zhang, J.; Chen, H.; Duan, Z.; Chen, K.; Liu, Z.; Zhang, L.; Yao, N.; Li, B. The Effects of Co-transplantation of Olfactory Ensheathing Cells and Schwann Cells on Local Inflammation Environment in the Contused Spinal Cord of Rats. *Mol. Neurobiol.* **2016**, *54*, 943–953. [CrossRef] [PubMed]

174. Wang, X.; Kuang, N.; Chen, Y.; Liu, G.; Wang, N.; Kong, F.; Yue, S.; Zheng, Z. Transplantation of olfactory ensheathing cells promotes the therapeutic effect of neural stem cells on spinal cord injury by inhibiting necroptosis. *Aging* **2021**, *13*, 9056–9070. [CrossRef] [PubMed]

175. Ao, Q.; Wang, A.; Chen, G.; Wang, S.; Zuo, H.; Zhang, X. Combined transplantation of neural stem cells and olfactory ensheathing cells for the repair of spinal cord injuries. *Med. Hypotheses* **2007**, *69*, 1234–1237. [CrossRef] [PubMed]

176. Deng, Y.; Liu, Y.; Zhu, W.; Bi, X.; Wang, Y.; Ye, M.; Zhou, G.-Q. The co-transplantation of human bone marrow stromal cells and embryo olfactory ensheathing cells as a new approach to treat spinal cord injury in a rat model. *Cytotherapy* **2008**, *10*, 551–564. [CrossRef]
154. Srivastava, N.; Seth, K.; Khanna, V.; Ansari, R.; Agrawal, A. Long-term functional restoration by neural progenitor cell transplantation in rat model of cognitive dysfunction: Co-transplantation with olfactory ensheathing cells for neurotrophic factor support. *Int. J. Dev. Neurosci.* **2009**, *27*, 103–110. [CrossRef] [PubMed]

155. Wang, Y.-C.; Xia, Q.-J.; Ba, Y.-C.; Wang, T.-Y.; Lin, N.; Zou, Y.; Shang, F.-F.; Zhou, X.-F.; Wang, T.-H.; Fu, X.-M.; et al. Transplantation of olfactory ensheathing cells promotes the recovery of neurological functions in rats with traumatic brain injury associated with downregulation of Bad. *Cytotherapy* **2014**, *16*, 1000–1010. [CrossRef] [PubMed]

156. Fu, X.-M.; Liu, S.-J.; Dan, Q.-Q.; Wang, Y.-P.; Lin, N.; Lv, L.-Y.; Zou, Y.; Zhou, X.; Wang, T.-H. Combined Bone Mesenchymal Stem Cell and Olfactory Ensheathing Cell Transplantation Promotes Neural Repair Associated with CNTF Expression in Traumatic Brain-Injured Rats. *Cell Transplant.* **2015**, *24*, 1533–1544. [CrossRef] [PubMed]

157. Liu, S.-J.; Zou, Y.; Belegu, V.; Lv, L.-Y.; Lin, N.; Wang, T.-Y.; McDonald, J.W.; Zhou, X.; Xia, Q.-J. Co-grafting of neural stem cells with olfactory en sheathing cells promotes neuronal restoration in traumatic brain injury with an anti-inflammatory mechanism. *J. Neuroinflammation* **2014**, *11*, 66. [CrossRef]

158. Zhai, W.; Gao, L.; Qu, L.; Li, Y.; Zeng, Y.; Li, Q.; Xu, H.; Yin, Z.Q. Combined Transplantation of Olfactory Ensheathing Cells with Rat Neural Stem Cells Enhanced the Therapeutic Effect in the Retina of RCS Rats. *Front. Cell. Neurosci.* **2020**, *14*, 52. [CrossRef]

159. Shi, X.; Kang, Y.; Hu, Q.; Chen, C.; Yang, L.; Wang, K.; Chen, L.; Huang, H.; Zhou, C. A long-term observation of olfactory ensheathing cells transplantation to repair white matter and functional recovery in a focal ischemia model in rat. *Brain Res.* **2010**, *1317*, 257–267. [CrossRef]

160. Tang, Z.-P.; Xie, X.-W.; Shi, Y.-H.; Liu, N.; Zhu, S.-Q.; Li, Z.-W.; Chen, Y. Combined Transplantation of Neural Stem Cells and Olfactory Ensheathing Cells Improves the Motor Function of Rats with Intracerebral Hemorrhage. *Biomed. Environ. Sci.* **2010**, *23*, 62–67. [CrossRef]

161. Carvalho, L.; Teng, J.; Fleming, R.L.; Tabet, E.; Zinter, M.; Reis, R.A.D.M.; Tannous, B. Olfactory Ensheathing Cells: A Trojan Horse for Glioma Gene Therapy. *JNCI J. Natl. Cancer Inst.* **2019**, *111*, 283–291. [CrossRef] [PubMed]

162. Chen, L.; Huang, H.; Zhang, J.; Zhang, F.; Liu, Y.; Xi, H.; Wang, H.; Gu, Z.; Song, Y.; Li, Y.; et al. Short-term outcome of olfactory ensheathing cells transplantation for treatment of amyotrophic lateral sclerosis. *Chin. J. Reparative Reconstr. Surg.* **2007**, *21*, 961–966.

163. Huang, H.; Chen, L.; Xi, H.; Wang, H.; Zhang, J.; Zhang, F.; Liu, Y. Fetal olfactory ensheathing cells transplantation in amyotrophic lateral sclerosis patients: A controlled pilot study. *Clin. Transplant.* **2008**, *22*, 710–718. [CrossRef] [PubMed]

164. Morita, E.; Watanabe, Y.; Ishimoto, M.; Nakano, T.; Kitayama, M.; Yasui, K.; Fukada, Y.; Doi, K.; Karunaratne, A.; Murrell, W.G.; et al. A novel cell transplantation protocol and its application to an ALS mouse model. *Exp. Neurol.* **2008**, *213*, 431–438. [CrossRef] [PubMed]

165. Giordana, M.T.; Grifoni, S.; Votta, B.; Magistrello, M.; Vercellino, M.; Pellerino, A.; Navone, R.; Valentini, C.; Calvo, A.; Chio, A. Neuropathology of Olfactory Ensheathing Cell Transplantation into the Brain of Two Amyotrophic Lateral Sclerosis (ALS) Patients. *Brain Pathol.* **2009**, *20*, 730–737. [CrossRef]

166. Piepers, S.; Berg, L.H.V.D. No benefits from experimental treatment with olfactory ensheathing cells in patients with ALS. *Amyotroph. Lateral Scler.* **2009**, *11*, 328–330. [CrossRef]

167. Chen, L.; Huang, H.; Xi, H.; Xie, Z.; Liu, R.; Jiang, Z.; Zhang, F.; Liu, Y.; Chen, D.; Wang, Q.; et al. Intracranial Transplant of Olfactory Ensheathing Cells in Children and Adolescents with Cerebral Palsy: A Randomized Controlled Clinical Trial. *Cell Transplant.* **2010**, *19*, 185–192. [CrossRef]

168. Ruitenberg, M.; Plant, G.W.; Christensen, C.L.; Blits, B.; Niclou, S.; Harvey, A.R.; Boer, G.J.; Verhaagen, J. Viral vector-mediated gene expression in olfactory ensheathing glia implants in the lesioned rat spinal cord. *Gene Ther.* **2002**, *9*, 135–146. [CrossRef]

169. Cao, L.; Liu, L.; Chen, Z.; Wang, L.; Ye, J.; Qiu, H.; Lu, C.; He, C. Olfactory ensheathing cells genetically modified to secrete GDNF to promote spinal cord repair. *Brain* **2003**, *127*, 535–549. [CrossRef]

170. Ma, Y.-H.; Zhang, Y.; Cao, L.; Su, J.-C.; Wang, Z.-W.; Xu, A.-B.; Zhang, S.-C. Effect of Neurotrophin-3 Genetically Modified Olfactory Ensheathing Cells Transplantation on Spinal Cord Injury. *Cell Transplant.* **2010**, *19*, 167–178. [CrossRef]

171. Carwardine, D.; Wong, L.-F.; Fawcett, J.W.; Muir, E.M.; Granger, N. Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC. *J. Neurol. Sci.* **2016**, *367*, 311–318. [CrossRef] [PubMed]

172. Johansson, S.; Lee, I.-H.; Olson, L.; Spenger, C. Olfactory ensheathing glial co-grafts improve functional recovery in rats with 6-OHDA lesions. *Brain* **2005**, *128*, 2961–2976. [CrossRef] [PubMed]

173. Zhang, J.; Chen, H.; Duan, Z.; Chen, K.; Liu, Z.; Zhang, L.; Yao, N.; Li, B. The Effects of Co-transplantation of Olfactory Ensheathing Cells and Schwann Cells on Local Inflammation Environment in the Contused Spinal Cord of Rats. *Mol. Neurobiol.* **2016**, *54*, 943–953. [CrossRef] [PubMed]

174. Wang, X.; Kuang, N.; Chen, Y.; Liu, G.; Wang, N.; Kong, F.; Yue, S.; Zheng, Z. Transplantation of olfactory ensheathing cells promotes the therapeutic effect of neural stem cells on spinal cord injury by inhibiting necroptosis. *Aging* **2021**, *13*, 9056–9070. [CrossRef] [PubMed]

175. Ao, Q.; Wang, A.; Chen, G.; Wang, S.; Zuo, H.; Zhang, X. Combined transplantation of neural stem cells and olfactory ensheathing cells for the repair of spinal cord injuries. *Med. Hypotheses* **2007**, *69*, 1234–1237. [CrossRef] [PubMed]

176. Deng, Y.; Liu, Y.; Zhu, W.; Bi, X.; Wang, Y.; Ye, M.; Zhou, G.-Q. The co-transplantation of human bone marrow stromal cells and embryo olfactory ensheathing cells as a new approach to treat spinal cord injury in a rat model. *Cytotherapy* **2008**, *10*, 551–564. [CrossRef]