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# Conversion of pericytes to neurons: a new guest at the reprogramming convention

Emmanuel Nivet, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte

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Emmanuel Nivet, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte. Conversion of pericytes to neurons: a new guest at the reprogramming convention. Stem Cell Research and Therapy, 2013, 4 (1), pp.2. 10.1186/scrt150. hal-01736196

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Distributed under a Creative Commons Attribution 4.0 International License
COMMENTARY

Conversion of pericytes to neurons: a new guest at
the reprogramming convention

Emmanuel Nivet¹, Ignacio Sancho-Martinez¹ and Juan Carlos Izpisua Belmonte*¹,²

**Abstract**

Reprogramming strategies allow for the generation of virtually any cell type of the human body, which could be useful for cell-based therapy. Among the different reprogramming technologies available, direct lineage conversion offers the possibility to change the phenotype of a cell type to another one without pushing cells backwards to a plastic/proliferative stage. This approach has raised the possibility to apply a similar process *in vivo* in order to compensate for functional cell loss. Historically, the cerebral tissue is a prime choice for developing cell-based treatments. As local pericyte accumulation is observed after central nervous system injury, it can be reasoned that this cell type might be a good candidate for the conversion into new neurons *in vivo*. In this article, and by focusing on recent observations from Karow and colleagues demonstrating the possibility to convert human brain-derived pericytes into functional neurons, we present a brief overview of the state of the art and attempt to offer perspective as to how these interesting laboratory findings could be translated in the clinic.

Reprogramming strategies are highly promising for the
development of future regenerative medicine approaches.
Over the past 60 years, from the first nuclear transfer
experiment to the description of cell fate conversions by
forced expression/inhibition of cell-type specific trans-
cription factors (TFs) and/or miRNAs, a great deal of evi-
dence showing cell identity switches has been accumu-
lated [1]. Numerous cocktails of TFs have to date been
identified for the conversion of somatic cells all the way
back to pluripotency or into more specialized cell types.
Accordingly, the emergence of cell fate conversion
strategies represents a new unexpected source for

generating any desired cell type that could be of interest
for the clinic. These lineage conversion strategies could
be divided into: direct conversion approaches, in which
tissue-specific TFs are employed and characterized by
the lack of proliferation and/or progenitor generation;
and indirect conversion approaches, based on the use of
so-called pluripotency factors. Indirect lineage conver-
sion, as opposed to direct conversion, is driven by a
partial dedifferentiation step, with potential for the
generation of expandable progenitor populations, followed
by redifferentiation into specific populations (for a recent
review see [1]).

Noticeably, cerebral tissue has always been one of the
most studied tissues for the development of cell-based
therapies, sustained by the hope that cell transplantations
could facilitate the replacement of lost neural tissue and/
or protect from neurodegenerative processes. Although
several cell types have demonstrated encouraging results
in animal models, neural stem cells and their derivatives
are naturally seen as the most suitable cellular products.
Taking into account that access to such cellular material
is technically and ethically difficult, the advent of lineage
conversion strategies has opened new vistas towards the
generation of neural cells as well as towards the
exploration of new treatment avenues.

In 2010 the Wernig laboratory was the first to meet this
challenge by defining a set of three TFs – that is, Ascl1,
Brn2 and Myt1l – allowing for the generation of
functional neurons upon overexpression in mouse fibro-
blasts [2]. Later on, the same group demonstrated that
addition of NeuroD1 to this cocktail was sufficient to
achieve the same conversion in human fibroblasts [3].
Numerous reports have since then reproduced and
extended this discovery by identifying other lineage
specifiers able to convert fibroblasts into neural pro-
genitors or more specialized neurons such as moto-
neurons [4] and dopaminergic neurons [5]. Alternatively,
by combining pluripotency-associated reprogramming
factors with neural specifiers or defined media, other
laboratories have reported that it is feasible to convert
fibroblasts into expandable neural stem cells [6].

From these and other reports, two main lineage
conversion strategies can be envisaged for clinical

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<footnote>*Correspondence: belmonte@salk.edu or izpisua@cmrb.eu
¹Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Full list of author information is available at the end of the article</footnote>
applications: the generation of the desired cell type(s) *in vitro* and its further transplantation; and the local *in vivo* conversion of one cell type into the one(s) required, in a similar way to what has been experimentally done with pancreatic cells. As a common denominator for most of these studies, however, fibroblasts represent the starting cell type of choice for achieving this lineage conversion; cord blood cells [7] and astrocytes [8] are exceptions to this rule. The latest strategy might thus not be the most appropriate unless other cell types present in the brain, and not as essential for brain functions as neural cells, could be reprogrammed.

Interestingly, a recent report from the Berninger labora-
tory convincingly extended the spectrum of somatic cell
types able to give rise to neurons upon forced expression
of TFs [9]. In their report, Karow and colleagues describe
the *in vitro* conversion of pericytes, residing in the adult
human brain, using only two TFs: Sox2 and Mash1
(Ascl1). The authors showed that the so-called human
pericyte-derived induced neurons acquired molecular
marks and electrophysiological properties resembling
those of primary mature neurons, with further matura-
tion when co-cultured with murine neurons. Even though
the final evidence for the phenotypic identity of the newly
generated neurons is not yet provided, they seem to
display the hallmarks of GABAergic interneurons. Of
note, the authors observed a conversion rate of about
20% but also an important cell death (≈30%) in the co-
transfected cells. Although the mechanism of action
controlling this lineage conversion is not fully identified,
Sox2 being a pluripotent factor as well as a neural lineage
specifier, a synergic effect may occur consisting of Sox2-
induced partial dedifferentiation alongside activating a
neuronal program with both Sox2 and Mash1. Of
importance, the authors showed that converted cells do
not undergo cell division during this process, supporting
the idea that this occurs via a direct conversion
mechanism.

In conclusion, pericytes not only represent a new cell
type suitable for neuronal conversion but also provide a
new cell candidate for *in vivo* approaches. Indeed, simi-
larly to astrocytes, pericytes have been identified as one
of the core components of post-injury scarification in the
central nervous system [10]. Considering that pericytes
are amenable to being converted into neurons, we can
imagine that these cells, localized within or close to an
injured area, may be a good target for *in vivo* conversion
without much effect on the surrounding neural cells.
However, it will be important to specifically convert
pericytes *in vivo* but also to limit the cell death associated
with this process. The role of resident pericytes after
injury should also be precisely studied to avoid any side
effect upon conversion. Importantly, both central
nervous system injuries and neurodegenerative processes

generally affect more than one cell type, implying that
several specialized cells counteracting the effects
observed in the diseased brain might be needed.

All in all, the study by Karow and colleagues presents
pericytes as a new contender in the race to the operating
room but we have a long way to go before a particular cell
type gets elected.

**Abbreviations**

miRNA, microRNA; TF, transcription factor.

**Competing interests**

The authors declare that they have no competing interests.

**Acknowledgements**

The authors thank May Schwarz for administrative support. The laboratory of JCIB is supported by grants from Fundacion Cellex, CIBER the G Harold and Leila Y Mathers Charitable Foundation, The Leona M and Harry B Helmsley Charitable Trust, and MINECO.

**Author details**

¹Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. ²Center for Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain.

Published: 11 January 2013

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doi:10.1186/scrt150

Cite this article as: Nivet E, et al.: Conversion of pericytes to neurons: a new guest at the reprogramming convention. *Stem Cell Research & Therapy* 2013 4:2.