(2022) 13:18
Li et al. Stem Cell Research & Therapy
https://doi.org/10.1186/s13287-021-02690-2

Open Access

REVIEW

Immunomodulatory effects of mesenchymal
stem cells in peripheral nerve injury
Xiangling Li1,2,4, Yanjun Guan2, Chaochao Li2, Tieyuan Zhang2, Fanqi Meng2,5, Jian Zhang2, Junyang Li2,6,
Shengfeng Chen2, Qi Wang1,4, Yi Wang3*, Jiang Peng2* and Jinshu Tang1*

Abstract
Various immune cells and cytokines are present in the aftermath of peripheral nerve injuries (PNI), and coordinationof the local inflammatory response is of great significance for the recovery of PNI. Mesenchymal stem cells (MSCs)
exhibit immunosuppressive and anti-inflammatory abilities which can accelerate tissue regeneration and attenuate
inflammation, but the role of MSCs in the regulation of the local inflammatory microenvironment after PNI has notbeen widely studied. Here, we summarize the known interactions between MSCs, immune cells, and inflammatory
cytokines following PNI with a focus on the immunosuppressive role of MSCs. We also discuss the immunomodulatory potential of MSC-derived extracellular vesicles as a new cell-free treatment for PNI.
Keywords: Mesenchymal stem cells (MSCs), Immunomodulation, Peripheral nerve injury, Review
Background
Peripheral nerve injury (PNI) refers to varying degreesof trauma to peripheral nerve stems or branches. PNI
accounts for 1.5–4.0% of global trauma cases annually [1] and is one of the most challenging health issues
at present. Nerve regeneration is a complicated cellular
process involving inflammation, neurotrophic factors,
neurotransmitters, adhesion, the formation of axons andgrowth cones, and the survival of neurons [2]. PNI triggers a series of immunoregulatory reactions in the cellular microenvironment, involving changes of immune cells
and related immunoregulatory factors. Immunomodulatory factors currently known include interleukin-1*Correspondence: wangyi1@301hospital.com.cn; pengjiang301@126.com;
drtang304@126.com
1
The Fourth Medical Center of Chinese PLA General Hospital,
Beijing 100853, People’s Republic of China
2
Institute of Orthopedics, Chinese PLA General Hospital, Beijing
Key Lab of Regenerative Medicine in Orthopedics, Key Laboratoryof Musculoskeletal Trauma & War Injuries PLA, Beijing 100853, People’s
Republic of China
3
Department of Stomatology, First Medical Center, Chinese PLA General
Hospital, Beijing 100853, People’s Republic of China
Full list of author information is available at the end of the article(IL-1α, IL-1β), IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17,
IL-6 [3, 4], tumor necrosis factor-a (TNF-α), indoleamine-2, 3-dioxygenase (IDO), interferon-γ (IFN-γ),transforming growth factor-beta1 (TGF-β1), heme oxygenase-1 (HO-1), hepatocyte growth factor (HGF), nitricoxide (NO), human leucocyte antigen-G5 (HLA-G5)
and prostaglandin E2 (PGE2) [5, 6].
Amongst other techniques, autologous nerve grafting,nerve conduit synthesis [7], stem cell transplantation[8], and exosome extraction [9] are currently more popular treatments for PNI. For peripheral nerve damageof more than 3 cm in length, autologous nerve grafting
is considered the gold standard treatment [10]. Stemcell transplantation is a novel method capable of regulating the inflammatory response which may accelerate
the transition from destructive to restorative inflammatory microenvironment [11] and has been confirmed
to promote the regeneration of peripheral and central
nerves [12]. Mesenchymal stem cells (MSCs) can produce a variety of immunoregulatory factors modulating the immune function of autologous and allogeneic
immune cells as well as innate (including natural killer(NK) cells[13], neutrophils, macrophages, mast cells,© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​
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Li et al. Stem Cell Research & Therapy(2022) 13:18

and dendritic cells (DCs)) and acquired immune cells(including T cells and B cells) [14] (Fig. 1). MSCs exert
their immunomodulatory role via two distinct mechanisms: secretion of cytokines, including IDO (human)or NO (mouse), PGE2, IL-4, IL-10, IL-12, and IFN-γ,
and TNF-α, in a paracrine manner, and direct contact
between cells [15]. The most important role of human
MSCs (hMSCs) following injury is their secretion of
bioactive molecules such as cytokines, chemokines, andgrowth factors, rather than their differentiation ability[16] and there are now several studies that have shownthat many of the beneficial effects attributed to stem
cell therapy may be mediated via paracrine mechanisms [17]. However, the immunomodulatory effects
exerted by MSCs after PNI are not entirely clear. In thisreview, we discuss the changes occurring in the inflammatory microenvironment after treatment of PNI with
MSCs and MSC-derived exosomes (exos), as well as
the immunomodulatory effects exerted by different
immune cells and inflammatory factors.

Page 2 of 13

MSCs exert immunomodulatory effects
by modulating cytokine expression
MSCs downregulate the expression of pro‑inflammatory
factors

It has been reported that MSCs can suppress the expression of a variety of inflammatory cytokines in different
diseases, such as IL-17, IL-1β, IL-6, IL-3, IL-8, IL-21,
IL-22, IL-7, IFN-γ, TNF-α, and IL-12, among others.
After PNI, pro-inflammatory factors such as IL-1, IL-2,
IL-6, and TNF-α are expressed during the first stage ofWallerian degeneration, which promotes the recruitment of macrophages within 2–3 days [18]. However,
the inflammatory response exerts different functions at
different timepoints following injury. Results by Mietto
et al. suggested that in the early stage of injury, proinflammatory cytokines such as IL-1β and TNF-α are
predominantly secreted by de-differentiated Schwann
cells (SCs) after losing contact with axons, which thenrecruit macrophages to the site of injury [19]. Chen et al.
found that pro-inflammatory cytokines surrounding the

Fig. 1 Paracrine immunomodulatory effects of MSCs on different immune cells. MSCs exhibited immunosuppressive effects on macrophages,
T-cells, B-cells, regulatory T-cells (Tregs), DCs, neutrophils, and NK cells through the secretion of various cytokines. MSCs could inhibit macrophagemigration and promoted a shift from M1 to M2 polarization

Li et al. Stem Cell Research & Therapy(2022) 13:18

Page 3 of 13

injured peripheral nerve were significantly increasedin the lymph nodes (LN), creating a pro-inflammatoryenvironment, thereby leading to autoimmune reactions
against peripheral nerve antigens [20]. MSCs exhibit
strong plasticity and can switch from the pro-inflammatory “MSC1” type to the anti-inflammatory “MSC2” type.
Following stimulation with pro-inflammatory factors
such as IL-1α, TNF-α, and IFN-γ, or after toll like receptor 3 (TLR3) activation, resting-state MSCs are polarized to the anti-inflammatory MSC2 type, producing
large amounts of NO/IDO and other immunoregulatory
factors and chemokines which play an immunosuppressive role by inhibiting the function of effector T cells andinducing the production of regulatory T cells (Treg cells)[14]. Moreover, Omi [21] et al. reported that DPSC transplantation can significantly reduce the expression of proinflammatory cytokines IL-1β and TNF-α and increase
M2 polarization and recruitment under the inflammatory condition of diabetic peripheral nerves. In addition,
among the numerous proinflammatory factors affectedby MSCs after PNI, IFN-γ, IL-1, TNF-α, IL-6, and IL-17
have been widely studied in peripheral nerve regeneration. Below is some simple summary of them.

exosomes may be a result of the inflammatory microenvironment [25].

MSCs suppress the expression of IFN‑γ

MSCs downregulate the secretion of TNF‑αPrevious studies have shown that low levels of IFN-γ canaccelerate the spread of stem cells. SCs exhibited higher
levels of proliferation and expression of elevated GDNF
levels when cultured in a medium containing IFN-γ [22].
Several studies have also shown that MSCs can suppress
the expression of IFN-γ. For instance, Aggarwal et al.
found that co-culture of different immune cells with
hMSCs resulted in an inhibition of IFN-γ expression andan increase in IL-4 secretion [23], increased the transition of pro-inflammatory Th1 cells to anti-inflammatoryTh2 cells, and facilitated the generation of CD25 + andCD4 + regulatory T cells. Other studies have proventhat IFN-γ can enhance the immunomodulatory capacity of MSCs. For instance, Kim [24] et al. reported that
IFN-γ-primed MSCs could not only upregulate the gene
expression of chemotactic factors cysteine-X-cysteine
chemokine ligand 9 (CXCL9), CXCL10, CC-chemokine
ligand 8 (CCL8), which may possess a significant potential to recruit leukocytes but also highly promote the IDO
expression through the JAK-STAT1 signaling pathway,
thereby contributing to the inhibition of T-cells mediated by MSCs. Domenis et al. suggested that the proinflammatory cytokines IFN-γ/TNF-α may improve theimmunomodulatory and anti-inflammatory potential
of exosomes released by adipose-derived mesenchymal
stem cells (AD-MSCs) promote macrophage polarization
toward the M2 type, and the authors also speculated thatthe immunomodulatory properties of AD-MSCs-derived

TNF can be regenerated by monocytes, macrophages,
and other immune cells such as DCs, B cells, activatedNK cells, and T cells [32]. Similar to IL-1β, TNF-α
reaches its secretory peak one day after PNI [28] In addition, TNF can promote nerve regeneration by controlling the number of neutrophils and IL-1β expression [33].
The proinflammatory microenvironment mediated by
TNF-α plays a significant role in the immunoregulatory
function of MSCs. For example, pre-treatment of MSCs
with TNF-α promotes the secretion of anti-inflammatory
cytokines including IL-10 and TGF-β, enhancing immunosuppression and inducing anti-inflammatory Tregs[34]. Inhibition of the TNF-α-TNFR2 signaling pathway
in MSCs caused a decreased IL-10 and TGF-β secretion,
while increasing secretion of TNF-α, INF-γ, IL-2, andIL-17 by effector T cells (Teffs) [35]. The protective functions mediated via the TNFα-TNFR2 pathway result incell proliferation and survival [36]. However, TNF-α has
also been shown to inhibit the function of MSCs in nerve
repair by activating the Wnt signaling pathway under certain circumstances [37].

MSCs decrease the expression of IL‑1

There are two types of IL-1, IL-1α, IL-1β. The basic function of IL-1α is to induce the generation of IL-6 andgranulocyte–macrophage colony-stimulating factor(GM-CSF) in fibroblasts in situ, which can be detected
within 2 to 5 h after an injury [26]. IL-1β may promote
nerve regeneration via the nuclear factor-κB (NF-κB)
signaling pathway [27]. Previous studies suggested that
there are low levels of IL-1β one hour after injury, but
one-day post-injury—before macrophage recruitment—
the secretion of IL-1β peaks [28], 6 and 24 h after injury,
the expression levels of IL-1β is 2 times and 10 times
higher than in the control groups [29, 30]. High levelsof IL-1β are maintained for several days [27], gradually
decreasing and finally returning to the baseline levels
around 14 days after PNI. MSCs can reduce IL-1 expression: for instance, a study by Chen et al. reported thatbone-marrow-derived MSCs significantly reduced theexpression of IL-1β in mice following spinal cord injury(SCI) [31].

MSCs reduce the expression of IL‑6

IL-6 is a pluripotent cytokine that not only can accelerate the proliferation and activation of effector T cells
through immunostimulation, but also regulate Treg
cells through immunosuppression [26, 38]. IL-6 is
not detected in intact nerves, but recent studies haveLi et al. Stem Cell Research & Therapy(2022) 13:18

revealed that the cytokine IL-6 is produced by macrophages and fibroblasts in the injured peripheral nerve[39], and its expression is regulated by TNF-α. After
sciatic nerve injury, macrophage-derived IL-6 levels are
increased within 2 h. In SCs, its expression is increased
within 3 h of injury and maintained for at least 21 days.
Co-culturing the facial nerve with BMSCs in vitro,
Ge et al. and found that BMSCs secrete high levels of
IL-6 to regulate the balance of CD4 + T cell subsets,
to achieve future treatment of facial nerve injury [40].
Baez-Jurado demonstrated that astrocytes co-cultured
with the conditioned medium from AD-MSCs reduced
the expression levels of IL-6, TNF-α, and GM-CSF
and increased the expression levels of neuroprotective
cytokines [41] to regulate brain inflammation. Moreover, GM-CSF has been shown to suppress inflammationand potentially improve the microenvironment toward
promoting the clearance of myelin debris by increasing
the expression of galectin-3 on SCs [42] and enablingaxonal regeneration [43]. GM-CSF plays a key role inthe development and maturation of DCs as well as in
the proliferation and activation of T-cells [44].
MSCs downregulate the expression of IL‑17

IL-17 is produced by activated CD4 + T cells andincreases the production of proinflammatory factors
and neutrophil mobilizing cytokines, such as TNF-α,
IL-1β, and G-CSF [45]. IL-17 has been shown to play a
crucial role in the regulation of inflammatory responses
in autoimmune diseases. IL-17 can promote the releaseof inflammatory factors TNF-α, IL-6, and IFN-γ [46].
IL-15 and IL-23, derived from dendritic cells and macrophages, respectively, are the most significant regulatory factors of the expression of IL-17A [47]. The
expression of these two factors increases on the firstday after sciatic nerve injury, and their peaks precede
the peak expression of IL-17A, suggesting that they
act as inducers of IL-17A after PNI. The expression of
IL-17A peaks on day 7 after PNI [48]. The infiltrationof inflammatory cells and levels of pro-inflammatory
cytokines surrounding the injury site were significantly
reduced in IL-17-knockout mice compared to controls
after partial sciatic nerve ligation was significantly
reduced, while the expression of anti-inflammatory
cytokines IL-10, IL-13, and enkephalin were increased.
Yining et al. found that BMSCs can promote the proliferation and differentiation of Th17 cells which secrete
IL-17 and in turn promote BMSC secretion of PGE2,
while high levels of PGE2 negatively regulate IL-17
secretion by Th17 cells [40].

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MSCs exert immunomodulatory effects after PNI
by increasing the expression of anti‑inflammatory factors

Following SCI, the anti-inflammatory factors IL-10 and
TGF-β can be detected after PNI following macrophage
recruitment [18], which can reduce the inflammatory
response and promote neural tissue regeneration [49].
The release of IL-4 and IL-13 by Th2 can accelerate theactivation of M2 macrophages, promote the expression of anti-inflammatory cytokines IL-10 and TGF-β,
and up-regulate the expression of extracellular matrix
protein, growth factor, and arginase [50]. Several studies have revealed that MSCs can promote the expression of anti-inflammatory factors. For instance, Alineet al. found that mice treated with Wharton’s jellyderived MSCs (WJ-MSCs) exhibited increased levels of IL-4, IL-10, IL-35, and TGF-β [51]. The authors
concluded hWJ-MSCs may regulate immune cell function via secretion of high levels of TGF-β and IL-35,
to adjust the inflammatory microenvironment to promote the recovery of the sciatic nerve. In this review,
we have focused on describing the main representative
anti-inflammatory factors IL-10 and IL-4. However, it
should be noted that IL-4 and IL-10 are not the sole
representatives after PNI.
MSCs increase the expression of IL‑10

IL-10 is a type of pro-regenerative cytokine. Increased
expression of IL-10 is associated with wound healing, tissue remodeling, and myelin regeneration [51]. It has beensuggested that the production and secretion of IL-10 are
induced by fibroblasts within 5 h after injury, but the lowlevels of IL-10 produced by fibroblasts are insufficient toaid substantial repair. To overcome this, recruited macrophages, who are the key cell type expressing IL-10, produce and secrete IL-10. mRNA levels of IL-10 increase
from the first day after the injury, increase significantly
on day 4, peak on day 7, and are maintained at high levels until day 14 [18, 53]. Protein expression of IL-10
gradually increases in the first two weeks after injury[53]. IL-10 can limit the expression of proinflammatory
cytokines IL-1, TNF-α, and IL-6, as well as Th1-derived
cytokines such as IL-2 and IFN-γ. Moreover, IL-10 regulates the differentiation and proliferation of macrophages,
T cells, and B cells [26]. Ydens et al. found that sciatic
nerve transection injury can induce an immunosuppressive response, increase levels of IL-10, and provide
a microenvironment conducive to macrophage polarization to M2 type [54]. Additionally, Obermajer et al. foundthat both IL-10 and HLA-G5 are essential for MSCmediated immunosuppression, and the two moleculesLi et al. Stem Cell Research & Therapy(2022) 13:18

exert synergistic effects[55], and can also enhance theanti-inflammatory potential of MSCs. Cui et al. showedthat BMSCs stimulated with IL-10 inhibit the expressionof TNF-α and IL-1β [56].
MSCs promote the expression of IL‑4

It is becoming increasingly clear that IL-4 is an important immunomodulatory cytokine. It can not only recruit
more macrophages but also promote macrophage M2
type polarization, which has the potential to promote
peripheral nerve regeneration [57]. MSCs expressing IL-4
can induce macrophage M2 polarization [11] and further
promote the expression of IL-4. In addition, M2 macrophages induced by IL-4 or the other anti-inflammatory
cytokines can suppress anti-inflammatory responses
and promote angiogenesis and axonal regeneration [58].
Ullah et al. found that the expression IL-4 and TGF-β
were reduced at 2 weeks after sciatic nerve injury whentreated with dental pulp-derived stem cells (DPSCs),
whose levels gradually increased at 8 and 12 weeks after
injury [59]. Moreover, Yagura et al. demonstrated thattransplanted MSCs could induce euronal cells to secrete
CCL5 binding to the macrophage surface, which induced
high levels of IL-4 expression to promote macrophage
polarization to type M2 [60].

Immunomodulatory effects of MSCs on immune
cells in PNI
MSCs promote macrophage polarization toward M2 type

During acute inflammation, macrophages can amplify the
inflammatory response and recruit additional immune
cells via phagocytosis of invading microorganisms [61].
Two to three days after an injury, blood-derived macrophages in the distal nerve begin to accumulate andreach their numbers peak around 7-14d after injury.
Macrophages infiltrating the injured nerve express andproduce a great number of cytokines such as CCL2 andTNF-α, IL-1α, and IL-1β, to promote the further recruitment of monocytes or macrophages [28, 62]. Both cellto-cell contact and secreted factors are essential for themodulation of macrophages by MSCs. It has been confirmed that MSCs can secrete a variety of growth factors, chemokines, as well as other signaling molecules
to regulate macrophage maturation, polarization, andproliferation [63, 64]. For instance, Zhong et al. reported
that BMSCs can secrete GDNF that converts microglial
destructive M1-phenotype into regenerative M2-phenotype for the suppression of neuroinflammation, possibly through the inhibition of NF-κB signaling pathway
and the promotion of the PI3K/AKT signaling pathway [65]. Additionally, several studies have shown that
MSCs can influence M1/M2 polarization. For example,
by co-culturing ADMSCs with human peripheral blood

Page 5 of 13

monocytes (PBMCs) to explore the effects of MSCinduced macrophages (iMΦ) on inflammation modulation, Heo et al. found that macrophages highly expressedM2 type markers, indicating that secreted factors derived
from MSCs promoted M2 polarization [66]. Using coculture of bone marrow-derived macrophages with
MSCs, Xu et al. found that MSCs significantly promoted
macrophage polarization from M1 to M2 [67]. MSCs
are thought to modulate activation and polarization ofmacrophages via four molecular pathways which downregulate the release of pro-inflammatory cytokines andaccelerate nerve repair and regeneration, including PGE2,
tumor-necrosis-factor-inducible gene 6 protein (TSG-6),
progesterone receptor (PR), and glucocorticoid receptors (GR). Chen et al. found that exosomes derived fromhuman umbilical cord-derived MSCs (hUC-MSCs) could
modulate macrophages towards M2 polarization [68].
Peruzzaro et al. showed that MSCs can change the ratioof classical to M2 macrophage/microglia phenotypes
following traumatic brain injuries (TBI), increasing the
proportion of M2 cells around the injury site [64]. Moreover, macrophages can also influence MSCs. For example, Ma et al. found that macrophages can inhibit the
proliferation and differentiation of ADSCs by secretingpro-inflammatory cytokines, mainly TNF-α and IL-1β[69]. Several studies have shown that NF-κB is a crucial
regulator of inflammatory signaling and molecular determinant of macrophage phenotype by inducing inflammatory mediators such as IL-1β, IL-6, TNF, IL-12, CXCL-8,
and cyclooxygenase (COX) [70]. John et al. proposed thatthe inhibition of NF-κB signaling macrophages could
activate neutrophils as a result of the reduced release ofproinflammatory cytokines [71].
In conclusion, MSCs can decrease the infiltration of
M1 macrophages and promote macrophage polarizationfrom M1 to M2 type, thereby reducing pro-inflammatory
and increasing anti-inflammatory cytokines.
MSCs reduce the expression of T lymphocytes

Similar to macrophages, T lymphocytes are essential
for peripheral nerve regeneration. T cells can regulate
nerve regeneration through a variety of mechanisms,
including the secretion of cytokines, release of growth
factors, or direct interaction with cells [72]. MSCs can
suppress the proliferation of activated T lymphocytes
in a dose-dependent manner, which is thought to be
mediated by the expression of IDO and COX2 [73].
MSCs have been proven to exhibit immunomodulatory
effects on T cells in vitro. For instance, MSC-conditioned medium promotes T-cell production of antiinflammatory cytokines TGF-β, IL-4, IL-10, NO, andIDO [74]. Heo et al. found that iMΦ strongly inhibited
T lymphocytes [66]. Furthermore, MSC also has beenLi et al. Stem Cell Research & Therapy(2022) 13:18

shown to exert immunosuppressive functions on T cells
in vivo. Siniscalco et al. found that hMSCs delivered
systemically via the tail vein decrease secretion levels ofIL-1β and IL-17 and increase expression levels of IL-10
and the CD206 macrophage marker in a mouse modelof neuropathic pain, thus the authors concluded that T
lymphocytes are associated with the production of proinflammatory cytokines IL-17 and IL-1β [75]. Alternatively, although T cells do not produce IL-4, they havebeen shown to recruit eosinophils that can express
IL-4, both in vivo and in vitro, to promote nerve regeneration [76]. MSCs can inhibit T cell proliferation bypromoting the multiplication of Tregs [77], and suppressing conventional T cells, converting them to Tregs[78]. Moreover, umbilical cord blood-derived MSCs
pretreated with IFN-γ could suppress the function of
mature dendritic cells, thus stimulating T-lymphocyte
proliferation after direct contact [79].
In summary, MSCs could reduce the inflammatory response by inhibiting T-cells proliferation andactivation.
MSCs promote the proliferation and differentiation of Treg
cells

MSCs transplantation promotes the expansion of Tregs
in injured tissues [80]. Maintaining the balance between
Tregs and inflammatory cytokines is an important
immunoregulatory role of MSCs. For instance, several
studies found that IL-6 combined with TGF-β can induce
Th17 cell differentiation, while TGF-β induces differentiation of Tregs [62]. Tregs produce proinflammatory
factors under certain conditions, but generally produce
anti-inflammatory cytokines such as IL-10, TGF-β, andIL-35, which participate in the immunosuppressive function of Tregs, promoting functional recovery of injured
peripheral nerve [81, 82]. TNF can not only reduce thesuppressive function of Treg cells, but also promote their
proliferation under certain conditions in vitro [83]. Alineet al. found that hWJ-MSC promotes higher expression
levels of anti-inflammatory cytokines IL-35 and TGF-β
in Tregs when compared with that in fibroblasts [51].
In the treatment of PNI, an increased level of IL-35 can
induce Tregs differentiation [84]. In addition interactingwith cytokines, Tregs can induce neutrophil apoptosis,
promote the expression of TGF-β1 and IL-10, and inhibit
neutrophil production of IL-6 to create anti-inflammatory conditions that favor tissue repair. Additionally,
IL-10 also can counteract Tregs [85]. Tregs contributeto the inhibition of monocyte secretion of inflammatory
factors that promote macrophage polarization toward
the M2 phenotype.

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Therefore, MSCs can induce the generation of Tregs
in the inflammatory microenvironment so as to inhibit
the immune response and attenuate the resultant
inflammation.
MSCs inhibit the activation of NK cells

Several studies have shown that MSCs may inhibit NK
cell proliferation and cytotoxic activity [86], including
suppression of proliferation of resting NK cells induced
by IL-2, the secretion of pro-inflammatory factors suchas TNF-α and IFN-γ, and their killing capacity on target
cells. The inhibitory effect of MSCs on NK cells is dosedependent and a significant inhibitory effect can only
be achieved by maintaining a high MSC/NK cells [87].
Noone et al. proposed that hUCMSCs can inhibit NK
cell activation via secretion of PGE2 [13]. Aggarwal et al.
found a statistically significant reduction in IFN-γ production after co-culture of hMSCs with IL-2-stimulated
NK cells [23]. Moreover, Qiang et al. found that co-culture of NK cells with DMSCs resulted in downregulation of perforin, IFN-γ, and TNF-α, and upregulation of
IL-4 and IL-10 in NK cells [88]. In addition, the interaction between M2 macrophages induced by MSCs and NK
cells can inhibit the expression of proteins related to NK
cell activation, such as NKp44, CD25, CD69, and IFN-γ.
Other studies have shown that IFN-γ can enhance theimmunomodulatory ability of MSCs. Considering thedevelopment time frame of adaptive immunity, if celltherapy is allowed to occur, NK cells may be the source ofIFN-γ of MSCs in vivo [86].

The immunomodulatory effects of MSCs combinedwith nerve conduits in the treatment of PNISome studies have suggested that stem cell transplantation combined with different nerve conduits may represent a promising strategy for the treatment of PNIs.
Acellular nerve allografts (ANAs) are the most widelyused biomaterials for nerve repair in the clinic. Recent
studies have revealed that in the use of ANAs for bridging
the nerve defects, T cells regulate the secretion of inflammatory cytokines within ANAs concerning the length of
the ANA. For instance, long ANAs (4 cm) trigger a lower
accumulation of T cells and cytokine levels of IFN-γ,
IL-2, IL-4, and IL-13 [21]. Deng et al. found that T cells
can regulate IL-4 by affecting eosinophils levels in ANAs[76]. ANAs combined with MSCs have been suggested tobe effective for the treatment of PNI, and the regulationof the inflammatory microenvironment surrounding the
injured nerve is currently being explored. For instance,
Fan [89] et al. demonstrated that BMSCs combined withxenogeneic acellular nerve grafts (xANGs) could better promote nerve regeneration, possibly by reducing

Li et al. Stem Cell Research & Therapy(2022) 13:18

the release of pro-inflammatory factors IL-2, IFN-γ, andTNF-α and increasing the secretion of IL-10 in lymphocyte supernatants and serum when compared with thosein the xANG group (5 mm). Yue et al used a 15 mm artificial nerve composed of epidermal neural crest stems
cells (EPI-NCSCs), extracellular matrix (ECM), and polylactic co glycolic acid (PLGA) to treat peripheral nerve
injury and found that after bridging with EPI-NCSCs,
the expression of anti-inflammatory cytokines IL-4 andIL-13 increased, while the expression of pro-inflammatory cytokines IL-6 and TNF-α decreased [90]. Sevendays after transplantation, M2 macrophages increased,
while M1 macrophages decreased. Moreover, the number of SCs promoting myelination increased significantly
21 days after transplantation, while the number of activated fibroblasts decreased, and the structural and functional recovery of those animals treated with EPI-NCSCs
was significantly better than in the DMEM blank control
group. Therefore, the authors concluded that the combination of ANA with MSCs provides an inflammatory
microenvironment suitable for sciatic nerve repair.

Immunomodulatory effects of MSC‑derived
extracellular vesicles in PNI
A large body of research suggests that the majority ofMSC-derived immunosuppressive effects are attributed
to the immunoregulatory properties of the MSC-derived
secretome, which is composed of a soluble component
and encapsulated extracellular vesicles (EVs): apoptotic
bodies, exosomes (exos), and microvesicles [91]. Dueto their low immunogenicity, EVs derived from MSC(MSC-EVs) are considered as an appealing cell-free therapy. Recent studies have revealed MSC-EVs may exertanti-inflammatory functions that are similar to MSCs,
and achieve their anti-inflammatory effects by reducing levels of inflammatory cytokines and enhancing
anti-inflammatory responses [92]. Ma et al. found that
hUCMSC-EVs can inhibit the expression of pro-inflammatory cytokines IL-6 and IL‐1β and up-regulate IL-10
expression to rebalance the inflammatory responses ina rat sciatic nerve injury model [93]. Sheng [94] et al.
reported that rats treated with MSCs-EV and miRNA22-loaded MSCs-EV (EV-miRNA-22) exhibited attenuated levels of pro-inflammatory factors TNF-α, IL-1β,
and IL-18, and both showed a good ability to promote
nerve regeneration, albeit the effect of EV-miRNA-22
was better than that of the EV group. On the other hand,miRNA-22 could inhibit the production and release of
inflammatory responses. In addition, MSC-EVs can also
exert immunomodulatory effects by modulating immune
cells. For example, MSC-derived small extracellular vesicles (sEVs) can enhance IL-10 and TGF-β expression by

Page 7 of 13

inhibiting T lymphocyte proliferation and promoting
their apoptosis, while decreasing the proportion of Th17
cells and increasing Treg cells in the spleen, leading to adecrease of IL-17 levels in serum [95]. Extracellular vesicles derived from CD73 modified hUC-MSCs can promote M2 macrophage polarization while decreasing theexpression of pro-inflammatory factors TNF-α, IL-1β,
and IL-6, and increasing the expression of anti-inflammatory factors IL-4 and IL-10 [96].
The immunomodulatory activity of MSC-Derived EVs
may be regulated by Hypoxia-inducible factor 1-alpha(HIF-1α) [97]. Over-expression of HIF-1α in MSCs canenhance their immunosuppressive ability in different
immune cell populations including DCs, monocytes, andNK cells [98]. Table 1 demonstrates the immunomodulatory effects of MSC-EVs for the attenuation of inflammatory diseases [80, 95, 99–128] (Table 1).

Conclusion and deficiency
MSCs are multipotent stem cells with multiple biological potentials and may represent an ideal option for celltherapy applications due to their regenerative and immunoregulatory functions [129]. The use of MSCs withinnate mechanistic features to mediate the local inflammatory response following PNI would both reduce lossof muscle mass and shift the microenvironment towards
a pro-regenerative rather than profibrotic phenotype[130]. Animal studies with intravenous reinfusion transplantation or local tissue injection of MSCs have foundthat these cells can quickly migrate to injury sites andlocalize to sites of information where they promote antiinflammatory and immune regulatory effects [131–133].
There is a correlation between higher MSCs survival andreduced levels of pro-inflammatory cytokines as well asa transformation in macrophages from M1 to M2 [134].
However, currently studies investigating the immunoregulatory mechanisms of MSCs for the treatment of
PNI are not comprehensive enough, and the functions
played by different immune cells and cytokines remain
to be studied. Moreover, the various pathways involvedin the mediation of MSC-derived benefits remain to be
explored. Stem cell transplantation studies are at thispoint predominantly in pre-clinical stages, with several
issues needing to be addressed. Although the effectiveness of MSCs/MSCs-EVs for the treatment of PNI has
been demonstrated many times in animal studies, there
are still few studies highlighting the exact therapeuticmechanisms, in particular relating to the immunoregulatory mechanisms exerted by MSCs/MSCs-EVs. Further
studies investigating the molecular mechanism underlying the beneficial effects of MSCs in the treatment of PNI
will provide new strategies for disease therapy.

Li et al. Stem Cell Research & Therapy(2022) 13:18

Page 8 of 13

Table 1 Immunomodulatory effects of MSC/MSC-EVs for the attenuation of inflammatory diseases
Disease model

Animal for In Vivo
study

MSC source

Effects on immune cells

Effects oncytokines

Signaling
pathway/related
exosomal cargoRef. No

Arthritis

In vitro

BMSCs,BMSCs-Exos

CD8 or CD4 T lymphocytes↓,
B lymphocytes↑

IFN-γ,TNF-α↓; IL-10↑ –

[99]

IBD

Mouse

OE-MSCs-Exos

the differentiation of Th1 andTh17 cells↓, Treg cells↑

IL-17, IFN-γ↓; TGF-β,
IL-10↑–[100]

hP-MSCs-EVs

–

–

[101]

MuSCs

M2
macrophages↑,macrophages
infiltration↓

IL-10, TGF-β↑; TNFα, IL-1β, IFN-γ and
IL-6 ↓

IL-6,IL-1β↓

–

[102]

IUAs

Rat

UC-MSC-derived
exosomes

M2 macrophage↑

IL-1β, IL-6 and TNFα↓; IL-10, TGF-β↑

–

[103]

Liver disease

Mouse

hUC-MSCs

CD4 and CD8 T cells↓

IFN-γ↓

–

[104]

ALI

Mouse

UC-MSCs

M2 macrophage↑
M1 macrophage↓

TNF-α, IL-1β and
IL-6↓

–

[105]

EAE

Mouse

BMSCs

T cells↓–

STAT1,STAT3,mTOR[106]

hUCMSC-EV

the leukocyte
infiltration↓,Tregs↑

IL-17a, TNF-α, andIFN-γ↓; IL-4, IL-10↑

–

[107]

Lung injury andfibrosis

Mouse, monkeys

hESCs

–

TNF-α, TGF-β1, IL-6,
IL-1β, GRO-α, IL-1α,
IL-3 and IL-8↓

–

[108]

Wound healing

Mouse

BMSCs

M2 polarization↑

IL-10↑; TNF-α↓

miR-223[109]

Skin defect

Mouse

hBMSCsM2 macrophages↑–

miR-150-5p

[110]

IVD

BovinehBMSCs

–

–

[111]

Renal injury

Mouse

BMSC-exos

infiltration of of macrophages↓

IL-6, IL-8 and TNF-α↓
TNF-α, IL-6 andIL-1β↓

CCL2

[112]

Renal Diseases

Rat

hUCMSC-Ex–

TNF-α, IL-6 andIL-1β↓

mTOR

[113]

cGVHD

Mouse

BMSC-exos

Th17 cells, CD4 + T cells↓,
Tregs↑

IL-17, IL-17a, IL-21,
IL-22 and IL-2↓;
IL-10↑

–

[114]

aGVHD

Mouse

BMSC-exos

CD8αDCs, CD11b cDCs↑; CD8, IL-2, TNF-α and IFNCD3CD4 T cells↓γ↓; IL-10↑

–

[115]

Heart allograft
rejection

Rat

IDO-BMSCs

Tregs↑, DC↓

–

[116]

CIA

Rat

hUCMSCs

T lymphocytes (proliferation↓, IL-17, TGF-β↓
apoptosis ↑), Th17 cell↓,Tregs↑

RORγt mRNA,Foxp3 [117]
mRNA

Mouse

hADMSCs

Tregs↑,the proliferation of T
cells↓

TNF-α, IL-1β andIL-6↓; IL-10↑

–

[80]

Rat

hUCMSC-sEVs

Th17 cell↓, T lymphocyte
proliferation↓, Tregs↑

–

[95]

PNI

Rat(MRI, LPS and
FK506)

GFP-BMSCs

M1,TLR4↓

IL-17↓; IL-10, TGF-β↑

TNF-α, IL-6↓; BDNF,
GDNF↑

–

[118]

PSNL

Rat(LPS)BMSCs–

IL-1β, TNF-α↓

–

[119]

CCI

Rat(PMF)

ADMSCs–IL-6, IL-1β↓; IL-10↑

–

[120]

Diabetic

Rat

DPSCs

CD206↑, CD68‐positive
monocytes/macrophages↓

TNF-α, IL-1β↓;IL-10↑–[121]

CCI and SNIMouse(TGF-β1)

BMSCS

–

Il-1β, IL-6 and TNFα↓; TGF-β1↑

–

[31]

Nerve injuryinduced pain

Rat

UCMSC -exos–

TNF-α, IL-1β↓

–

[122]

Dysphagia

Rat

hDPSCsM2 macrophages↑

iNOS, IL-1β↓

–

[123]

IL-10, TGF-β1, TGFβ2 and TGF-β3↑;IL-2, IFN-γ↓

Li et al. Stem Cell Research & Therapy(2022) 13:18

Page 9 of 13

Table 1 (continued)
Disease model

Animal for In Vivo
study

MSC source

Effects on immune cells

Effects oncytokines

Signaling
pathway/related
exosomal cargoRef. No

TBI

Rat

MSCs

M1 macrophage↓, M2 macrophages↑

IL-10↑; IL-1β, IL-6,
IL-17, IFN-γ and
TNF-α↓

NF-κB

[124]

DAH

Mouse

hUCMSC-Ex

M1 macrophage↓, M2 macrophages↑

IL-6, TNF-α↓; IL-10,
TGF-β↑–[125]

Skeletal muscle
contusion

Mouse and in vitro

hBMSC-exos

M1 macrophages ↓, M2
macrophages↑

IL-6, TNF-α↓;IL-10,TGF-β↑

–

[126]

SCI

Mouse

hUCMSCs

M2 macrophages↑

IL-7, IFN-γ, and TNFα↓; IL-4, IL-13↑

–

[127]

PF

Mouse

hUCMSCs

Tregs↑CXCL9, CXCL10↑

–

[128]

Effect of MSCs on cytokines and immune cells when treating different diseases. BMSCs: bone marrow-derived mesenchymal stem cells; OE-MSCs: Olfactoryecto-mesenchymal stem cells; IBD: inflammatory bowel disease; IUAs: intrauterine adhesions; UC-MSC: umbilical cord-derived mesenchymal stem cell; ALI: acutelung injury; EAE: experimental autoimmune encephalomyelitis; hESCs: human embryonic stem cells; hP-MSCs-EVs: human placental mesenchymal stem cellsderived EVs; hUCMSC-Ex: human umbilical cord MSC-derived exosomes; cGVHD: chronic Graft-Versus-Host Disease; aGVHD: acute graft-versus-host disease; cDCs:
the CD8α conventional dendritic cells; IDO-BMSCs: BMSCs which stably expressed IDO; CIA: collagen-induced arthritis; NCI: nerve crush injury: MRI: magnetic
resonance imaging; PSNL: partial sciatic nerve ligation; CCI: chronic constriction nerve injury model; ADMSC: adipose tissue derived mesenchymal stem cells;
PMF: pulsed magnetic field; DPSCs: Dental pulp-derived stem cells; SNI: spared nerve injury; TBI: traumatic brain injury; DAH: diffuse alveolar hemorrhage; MuSCs:
muscle stem cells; SCI: spinal cord injury; hUCSC-EV: Human umbilical cord mesenchymal stem cell-derived extracellular vesicles; EAE: experimental autoimmune
encephalomyelitis; PF: Pulmonary fibrosis; RA: Rheumatoid arthritis; hUCMSC-sEVs: hUCMSC-derived small extracellular vesicles (sEVs)

Abbreviations
PNI: Peripheral nerve injuries; MSCs: Mesenchymal stem cells; TNF-α: Tumor
necrosis factor-α; IL: Interleukin; IFN: Interferon; TGF: Transforming growth
factor; HO: Heme oxygenase; HGF: Hepatocyte growth factor; NO: Nitricoxide;
HLA-G5: Human leucocyte antigen-G5; PGE: Prostaglandin E; NK: Naturalkiller; DCs: Dendritic cells; exos: Exosomes; SCs: Schwann cells; LN: Lymphnodes; TLR: Toll like receptor; Treg cells: Regulatory T cells; GDNF: Glial cell
derived neurotrophic factor; CXCL: Cysteine-X-cysteine chemokine ligand;
CCL: Cellular components chemokine ligand; BMSCs: Bone marrow-derived
mesenchymal stem cells; ADMSCs: Adipose tissue derived mesenchymal
stem cells; GM-CSF: Granulocyte–macrophage colony-stimulating factor;
NF-κB: Nuclear factor-κB; SCI: Spinal cord injury; Teffs: Effector T cells; WJ:
Wharton’s jelly; DP: Dental pulp; PBMCs: Peripheral blood monocytes; TSG-6:
Tumor-necrosis-factor-inducible gene 6 protein; PR: Progesterone receptor;
GR: Glucocorticoid receptors; hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; TBI: Traumatic brain injuries; COX: Cyclooxygenase; ANAs:
Acellular nerve allografts; xANGs: Xenogeneic acellular nerve grafts; EPI-NCSCs:
Epidermal neural crest stems cells; ECM: Extracellular matrix; PLGA: Polylactic
co glycolic acid; EVs: Extracellular vesicles; OE-MSCs: Olfactory ecto-MSCs; IBD:
Inflammatory bowel disease; IUAs: Intrauterine adhesions; ALI: Acute lunginjury; EAE: Experimental autoimmune encephalomyelitis; hESCs: Humanembryonic stem cells; hP-MSCs-EVs: Human placental mesenchymal stem
cells-derived EVs; hUCMSC-Ex: Human umbilical cord MSC-derived exosomes;
mTOR: Mammalian target of rapamycin; cGVHD: Chronic Graft-Versus-Host
Disease; aGVHD: Acute graft-versus-host disease; cDCs: The CD8α conventional dendritic cells; IDO-BMSCs: BMSCs which stably expressed IDO; CIA:
Collagen-induced arthritis; NCI: Nerve crush injury; MRI: Magnetic resonanceimaging; Foxp3: Forkhead box protein P 3; PSNL: Partial sciatic nerve ligation;
CCI: Chronic constriction nerve injury model; PMF: Pulsed magnetic field;
DPSCs: Dental pulp-derived stem cells; SNI: Spared nerve injury; TBI: Traumaticbrain injury; DAH: Diffuse alveolar hemorrhage; MuSCs: Muscle stem cells;
hUCSC-EV: Human umbilical cord mesenchymal stem cell-derived extracellular vesicles; PF: Pulmonary fibrosis; RA: Rheumatoid arthritis.
Acknowledgements
We thank Prof. Yu Wang (Institute of Orthopedics) for her patient guidance inrevising this review. And this work was supported by Medical Research andDevelopment Projects (AWS17J005).

Authors’ contributions
JST performed most of the overall work for this report. YW, JP contributed to
the review of mesenchymal stem cell therapy as co-corresponding authors.
LXL contributed to the review of mesenchymal stem cell applications inperipheral nerve injury. YJG, FQM, CCL contributed to the review of animalstudies concerning mesenchymal stem cell therapy and wrote much of thismanuscript. TYZ, JYL, JZ contributed to the review of the history of mesenchymal stem cell therapy in different diseases. SFC, YLL, QW contributed to
the review of the application aspects of mesenchymal stem cell therapy. All
authors read and approved the final manuscript.
Funding
This work was supported by Medical Research and Development Projects(AWS17J005).
Availability of data and materials
Not applicable.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
The Fourth Medical Center of Chinese PLA General Hospital, Beijing 100853,
People’s Republic of China. 2 Institute of Orthopedics, Chinese PLA General
Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing 100853, People’s
Republic of China. 3 Department of Stomatology, First Medical Center, Chinese
PLA General Hospital, Beijing 100853, People’s Republic of China. 4 The Schoolof Medicine, Jinzhou Medical University, Jinzhou 121099, People’s Republicof China. 5 Department of Spine Surgery, Peking University People’s Hospital,
Beijing 100044, People’s Republic of China. 6 The School of Medicine, Nankai
University, Tianjin 300071, People’s Republic of China.

Li et al. Stem Cell Research & Therapy(2022) 13:18

Page 10 of 13

Received: 22 October 2021 Accepted: 18 December 2021
22.
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