A recent PLoS Biology report from Meletis et al. (2008) strongly suggests that ependymal cells are a key source of endogenous stem cells in the spinal cord. Advances in understanding endogenous neural stem cells may facilitate repair of the injured central nervous system

Fehlings, Michael G.

Hawryluk, Gregory W.J.

Elsevier - Publisher Connector 

The Center of the Spinal Cord May Be Central to Its Repair 

addition, other stem cells, for example,
neural or hematopoietic stem cells, ap-
pear to reside in perivascular locations
in situ (Hirshi and D’Amore, 1996). Since
MSCs isolated from different tissues ex-
hibit distinct sensitivities to inductive bio-
active molecules in culture, it follows that
this reactivity reflects the tissue of origin.
Most well studied are the adult marrow-
derived MSCs, which are often used as
the standard. The inductive conditions for
marrow MSCs are quite different from
those requiredby fat-derivedMSCs (Estes
etal., 2006),asmaybeexpecteddue to the
diversemicroenvironments present on the
tissue side of the vasculature in which the
pericytes reside. The MSCs from marrow
and fat arebothmultipotent, but the induc-
tive stimulus, TGF-b, for chondrogenesis
for marrow MSCs must be supplemented
with BMP-6 for fat MSCs. Clearly, such
variation in inductive requirements must
be taken into account when designing
expansion and differentiation protocols
for use in future therapeutic applications.
Although my colleagues and I have
been working with marrow MSCs for
over 20 years and have published on
markers of MSCs, their perivascular local-
ization in human skin, their multipotency,
and their secretion of bioactive factors
(Caplan, 2007), we and others have never
performed a comprehensive and detailed
comparison of the in situ and in vitro traits
of MSCs and pericytes. The team led by
Bruno Pe´ault provides a solid set of ob-
servations that clearly links the MSC and
pericyte. There will be a number of excep-
tions, but my suggestion is that all MSCs
are pericytes, and this manuscript gives
a formal context to better understand, in
both embryos and adults, how the MSC/
pericyte contributes to the formation,
maturation, and homeostasis of all vascu-
larized tissues.
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Cell Stem Cell
PreviewsThe Center of the Spinal Cord
May Be Central to Its Repair
Gregory W.J. Hawryluk1,2 and Michael G. Fehlings1,2,3,*
1Division of Genetics and Development, Toronto Western Research Institute, Institute of Medical Science, University of Toronto
2Division of Neurosurgery, University of Toronto
3Neural Repair and Regeneration, Spinal Program, University Health Network
Toronto Western Hospital, McLaughlin Pavilion, Room 407, 12th Floor, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada
*Correspondence: michael.fehlings@uhn.on.ca
DOI 10.1016/j.stem.2008.08.009
A recent PLoS Biology report from Meletis et al. (2008) strongly suggests that ependymal cells are a key
source of endogenous stem cells in the spinal cord. Advances in understanding endogenous neural stem
cells may facilitate repair of the injured central nervous system.Repair of the injured spinal cord is one of
the ‘‘holy grails’’ of medicine. The devel-
opment of strategies to protect and repair
the injured spinal cord has been facilitated
by the identification of key mechanisms of
secondary injury, by the characterization
of extrinsic barriers to axonal regenera-
tion, and by the discovery of neural stem
cells within the adult central nervous sys-
tem (CNS) (Rossignol et al., 2007).230 Cell Stem Cell 3, September 11, 2008 ªComplex and interrelated secondary
injury processes are now increasingly
understood, and they provide many po-
tential targets for therapeutic intervention.
Also critical has been the discovery that
central axons are capable of regenerating
but are prevented from doing so by inhib-
itory molecules expressed on central
myelin and in the postinjury extracellular
matrix (Rossignol et al., 2007). These dis-2008 Elsevier Inc.coveries have led to treatments now in
early-stage human clinical trials (Figure 1)
(Baptiste and Fehlings, 2008).
Neural precursor cells are emerging
as another potential means to repair the
injured CNS (Karimi-Abdolrezaee et al.,
2006). The precise source(s) of endoge-
nous neural precursor cells has been
controversial; however, in the brain, evi-
dence supports a role for cells in both
Cell Stem Cell
PreviewsFigure 1. Strategies to Protect andRepair the Injured Cord Currently in HumanClinical Trials
Experimental therapies are grouped into those aimed to induce neuroprotection or to promote regenera-
tion. Early decompression of the spinal cord is being examined in the Surgical Treatment for Acute Spinal
Cord Injury Study (STASCIS) as well as in a study of cerebrospinal fluid drainage. Systemic hypothermia is
being examined by theMiami Project to Cure Paralysis. Both decompression and hypothermia target mul-
tiple secondary injury mediators. Pharmacological approaches include riluzole, which targets excitotox-
icity as well as sodium dysregulation, and minocycline, which targets apoptosis and neuroinflammation.
Electrical field stimulation aims to promote axonal regeneration. Cells such as bone marrow stromal cells
and olfactory ensheathing cells are being transplanted into the injured spinal cord in centers outside of
North America. Antagonists of CNS axonal growth inhibitors include ATI-355, which sequesters the myelin
inhibitor Nogo, and Cethrin, which inhibits Rho, a downstream molecule involved in the signaling of all
known CNS inhibitors. Thank you to Derek Chew for assistance in constructing this figure.the ependymal and subependymal
layers, with many favoring a predominant
role of radial glial cells. The spinal cord
may have a unique source of neural pre-
cursor cells, as its ependymal layer,
unlike in the brain, exhibits greater prolif-
eration than its subependymal layer
(Adrian and Walker, 1962; Namiki and
Tator, 1999).
A recent publication from the Frisen
laboratory (Meletis et al., 2008) represents
a significant advance in determining the
source of neural stem cells in the spinal
cord. In order to define the origin of neural
stem cells in the region of the central
canal of the spinal cord, Frisen’s team
generated two transgenic mouse lines
expressing tamoxifen-dependent Cre re-
combinase under the control of FoxJ1 or
Nestin regulatory sequences. FoxJ1 is a
specific marker of cells with motile cilia
or flagella, whereas Nestin is expressed
by neural stem/progenitor cells. By label-
ing and characterizing spinal cord cells
with motile cilia using these novel trans-
genic mice, Frisen’s team provides con-
vincing evidence that ependymal cellsare the predominant source of endoge-
nous spinal cord stem cells.
There are several significant implica-
tions of these findings. First, harvesting
ependymal-derived neural precursor cells
for subsequent transplantation into the
injured cord may be preferable to other
donor cell types. This hypothesis is sup-
ported by data suggesting that trans-
planting cells and tissue to the anatomical
site from which they were isolated may
yield optimal results (Shetty and Turner,
2000). Perhaps specific cell populations
are best equipped to survive and function
in their original microenvironments. Sec-
ond, stimulating endogenous ependymal
cells within the injured spinal cord may
be preferred over transplanting exoge-
nous cells, as the latter may cause injury
and also require immunosuppression.
Future research will need to explore both
possibilities, and the transgenic animals
developed by Meletis and colleagues are
ideally suited for such experiments.
Also important is the finding that, fol-
lowing injury, ependymal cells not only
form myelinating oligodendrocytes butCell Stem Cell 3, Sealso differentiate preferentially into ‘‘as-
trocyte-like’’ cells that participate in astro-
glial scarring (Meletis et al., 2008). While
astrogliosis restricts the spread of dam-
age, it creates a physical and chemical
barrier to axonal outgrowth. Moreover,
work by Hofstetter et al. suggests that
astrocytic differentiation of transplanted
cells may exacerbate neuropathic pain
(Hofstetter et al., 2005). Indeed, much re-
mains to be learned about astrogliosis,
and this publication corroborates emerg-
ing evidence that the function of the astro-
glial scar is complex. Of interest, the
ependymal-derived astrocyte-like cells
observed by Meletis et al. appeared to
support axonal outgrowth, in contrast to
other regions of scar suggesting further
benefit to stimulating the proliferation of
these endogenous progenitor cells.
Additional areas for future research
are apparent. The transgenic animals em-
ployed in these experiments can deter-
mine if ependymal cells function as neural
stem cells in the brain and also determine
if they generate the more proliferative pre-
cursor cells in the brain’s subependymal
layer. As well, Meletis et al. (2008) suggest
that novel molecules may guide the mi-
gration of the ependymal progenitor cells;
once identified, the migration-inducing
pathways might be exploited to promote
repair.
It is important to place the work of
Meletis et al. (2008) into a broader con-
text. It is becoming increasingly apparent
that a combination of therapies will be
required to achieve clinically meaningful
improvements in spinal cord function.
While the stimulation of endogenous stem
cells is an attractive strategy for CNS
repair/regeneration, it is unclear whether
sufficient cells can be mobilized to pro-
vide efficient neural regeneration. Hence,
cell replacement approaches remain an
attractive cornerstone for combinatorial
therapies that are being considered for
clinical translation. Indeed, the replace-
ment of lost cells has shown promise in
various animal models of CNS injury.
Some researchers have sought and
achieved neural replacement with integra-
tion of transplanted cells into functional
circuits. Other groups, such as our own,
have sought and achieved oligodendro-
cytedifferentiationand remyelination (Kar-
imi-Abdolrezaee et al., 2006). A broad ar-
ray of cell types have been administered
in protocols designed toward achievingptember 11, 2008 ª2008 Elsevier Inc. 231
Cell Stem Cell
Previewsdiversegoals, andbenefit hasbeenalmost
universally reported. The benefit, how-
ever, has also been universally modest.
The relatively modest effects of cell re-
placement strategies undoubtedly stem
from the fact that these approaches are
currently employed with insufficient un-
derstanding of the mechanisms underly-
ing their observed benefit. Replacement
of lost cells likely plays an important
role, but functional improvement has
also been seen in the absence of this
effect. This has raised the possibility that
transplanted cells may secrete trophic
factors, or optimize the postinjury envi-
ronment, in order to facilitate neuropro-
tection or enhanced plasticity of surviving,
endogenous cells (Ourednik and Oured-
nik, 2004; Shetty and Turner, 2000). One
must also consider that different donor
cell types may lead to beneficial out-
comes through distinct mechanisms.
Studies exploring these possibilities are
critically needed to advance the field of
spinal repair. With improved understand-
ing of the biology of transplanted cellsTurning Back Tim
Pathology to Enha
Thomas A. Rando1,*
1Department of Neurology and Neurological S
Stanford, CA 94305-5235, USA
*Correspondence: rando@stanford.edu
DOI 10.1016/j.stem.2008.08.006
Histopathologic changes in disease
stem cells. A recent report in Nat
dystrophic mouse muscles with tis
and enhanced stem cell engraftme
Stem cell transplantation holds great
promise for the treatment of degenerative
diseases. The success of stem cell trans-
plantation depends not only the intrinsic
properties of the transplanted cells, but
also on the properties of the tissue into
which the cells will be introduced. It
seems to be generally true that exoge-
nous stem cells engraft farmore efficiently
into tissues, whether normal or diseased,
232 Cell Stem Cell 3, September 11, 2008 ªand their interaction(s) with the host
CNS, it may be possible to alter the exog-
enous cells and/or host environment in
order to augment functional recovery.
Enhanced knowledge of neural stem
cell biology, such as the advances pro-
vided by Meletis et al. (2008), will be key
to using neural precursor cells for CNS
repair and regeneration. Also key will be
an increased understanding of the sig-
naling pathways that underlie the differen-
tiation of neural stem cells, as recently
described by Whittemore’s group (Cheng
et al., 2007).
In conclusion, the work by Meletis et al.
(2008) represents an important step for-
ward in understanding the biology of en-
dogenous neural stem cells in the CNS.
It is fascinating to consider that the cells
at the center of the spinal cord may play
a central role in its repair.
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and VA Palo Alto Health Care Systems,
ble to engraftment by transplanted
emonstrates that pretreatment of
ed fibrosis, increased vascularity,
ate, and differentiate into mature tissue
may be severely compromised. In the
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The Center of the Spinal Cord May Be Central to Its Repair

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