The n e w e ng l a n d j o u r na l of m e dic i n e

Cl inic a l I m pl ic a t ions of B a sic R e se a rch

Elizabeth G. Phimister, Ph.D., Editor

Spinal Cord Injury — Healing from Within

Michelle Monje, M.D., Ph.D.

Spinal cord injuries are devastating, typically re-
sulting in lifelong neurologic deficits. The spinal
cord exhibits limited functional repair despite
the presence of endogenous ependymal stem cells
lining the central canal throughout the cord.
Loss of oligodendrocytes after a spinal cord in-
jury results in demyelination or dysmyelination
that impairs propagation of action potentials
in remaining or regenerated axons. In addition
to facilitating fast neural impulse conduction,
myelinating oligodendrocytes also provide meta-
bolic support for axons.1 Promoting myelin re-
generation from an endogenous cell population
therefore represents an experimental approach
to mitigating functional neurologic impairments
in spinal cord injuries.
In a recent study, Llorens-Bobadilla and col-
leagues investigated whether endogenous epen-
dymal stem cells are a source of myelin-forming
oligodendrocytes after a spinal cord injury.2
Ependymal stem cells are activated by spinal
cord injury: they migrate to the site of the injury,
where they differentiate into reactive astrocytes.3
Astrocytes are associated with glial scar forma-
tion and promote regeneration of axons after a
spinal cord injury.4 However, few oligodendro-
cytes are generated by ependymal cells, and resi-
dent oligodendrocyte precursor cells do not
generate sufficient numbers of myelinating oli-
godendrocytes to replace those lost after injury.
Using single-cell genomic and epigenomic
techniques, the authors identified transcrip-
tional programs and chromatin accessibility in
cellular populations of healthy and injured spi-
nal cords of mice. This approach uncovered a
latent genetic regulatory program for oligoden-
drogenesis in ependymal cells of the spinal cord.
The gene encoding a transcription factor called
Olig2, a master regulator of oligodendrogenesis,
is not normally expressed in ependymal cells.
Although the Olig2 target gene loci exhibit open
chromatin that is permissive to expression, the
target genes are not expressed in ependymal
cells in healthy, uninjured mouse spinal cords or
in injured spinal cords. This suggests a latent
ependymal cell capacity for oligodendrogenesis
and supports the hypothesis that inducing Olig2
expression in these cells will generate myelinat-
ing oligodendrocytes.
The authors therefore genetically engineered
the expression of Olig2 in ependymal cells in
mouse models of incisional and contusion spinal
cord injuries. As anticipated, injury to the spinal
cord triggered the recruitment of ependymal
cells to the injury site.3 Olig2-expressing ependy-
mal cells exhibited a rapid increase in the acces-
sibility of oligodendroglial lineage genes, Olig2
localization at its gene targets, and transcription
of oligodendroglial lineage gene programs after
the injury. These Olig2-expressing ependymal
cells generated numerous mature, myelinating
oligodendrocytes at the injury site over the
course of several weeks. In the absence of injury,
Olig2-expressing ependymal cells did not show
changes in chromatin accessibility or transcrip-
tion. They maintained normal morphologic fea-
tures and remained localized to the central canal
of the spinal cord.
The authors concluded that Olig2 expression
activates the latent oligodendrocyte lineage pro-
gram in ependymal cells when a spinal cord
injury occurs, and Olig2-expressing ependymal
cells generate a large number of oligodendrog-
lial cells (Fig. 1) and astrocytes. This oligoden-
droglial lineage population derived from epen-
dymal cells continued to self-propagate 3 months
after injury, and it is conceivable that, after an
injury to the spinal cord, ependymal-derived

182 n engl j med 384;2  nejm.org  January 14, 2021

The New England Journal of Medicine

Downloaded from nejm.org at MONASH UNIVERSITY LIBRARY on February 14, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
 Clinical Implications of Basic Research

A Oligodendrogenesis through Activation of Latent Genetic Program in Ependymal Cells

Olig2 Sox10 Myrf Oligodendrogenesis

DNA
Sox10 Olig2 Myrf Sox10 Myelin genes

Incisional or contusion injury

increases accessibility of enhancers of
“oligodendrogenesis” genes to Olig2

B
CENTRAL
Olig2-expressing CANAL Incisional or
contusion
Oligodendrocyte
ependymal cells
injury precursor cell

SPINAL CORD
TISSUE

Normal
astrocyte Myelinating
production oligodendrocyte

Compact myelin
formation

Astrocyte

Damaged neuron
Improved axon
conduction velocity
post-injury

SITE OF INJURY

Figure 1. Olig2 Expression Reprogramming Ependymal Cells to Produce Myelinating Oligodendrocytes after Spinal Cord Injury.
Expression of Olig2 recruits a latent program for oligodendrogenesis in ependymal cells (Panel A). Olig2 reprogramming in ependymal
cells (Panel B) results in differentiation into oligodendrocyte precursor cells and mature, myelinating oligodendrocytes that contribute
to regeneration after spinal cord injury in a mouse model. (Dr. Belgin Yalcin helped to conceptualize an earlier version of this figure.)

oligodendroglial lineage cell precursors could
maintain a reservoir of stem cells and renew
mature oligodendrocytes. It is important to note
that ependymal-derived oligodendrocytes my-
elinated spared axons after the spinal cord in-
jury, even when Olig2 expression was induced
after the injury. Reprogrammed ependymal cell–
derived myelination resulted in improved con-
duction velocity through the injured spinal cord
and thus represents an experimental strategy to
promote functional recovery after spinal cord
injury.
A pressing question is how to translate these
findings to persons with spinal cord injuries.
Olig2 gene transfer to ependymal cells, perhaps
with viral gene-transfer strategies similar to

n engl j med 384;2 nejm.org January 14, 2021 183

The New England Journal of Medicine
Downloaded from nejm.org at MONASH UNIVERSITY LIBRARY on February 14, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
 Clinical Implications of Basic Research

those in clinical development for neurodegener-
ative diseases of the spinal cord,5 could be con-
sidered. Until then, these new insights provide
hope that endogenous repair may one day ame-
liorate devastating neurologic injuries.
Disclosure forms provided by the author are available at
NEJM.org.
From Stanford University, Stanford, CA.
1. Fünfschilling U, Supplie LM, Mahad D, et al. Glycolytic oli-
godendrocytes maintain myelin and long-term axonal integrity.
Nature 2012;​485:​517-21.
2. Llorens-Bobadilla E, Chell JM, Le Merre P, et al. A latent
lineage potential in resident neural stem cells enables spinal
cord repair. Science 2020;​370(6512):​eabb8795.
3. Barnabé-Heider F, Göritz C, Sabelström H, et al. Origin of
new glial cells in intact and injured adult spinal cord. Cell Stem
Cell 2010;​7:​470-82.
4. Anderson MA, Burda JE, Ren Y, et al. Astrocyte scar forma-
tion aids central nervous system axon regeneration. Nature
2016;​532:​195-200.
5. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-
replacement therapy for spinal muscular atrophy. N Engl J Med
2017;​377:​1713-22.
DOI: 10.1056/NEJMcibr2030836
Copyright © 2021 Massachusetts Medical Society.

early job alert service available at the nejm careercenter

Register to receive weekly email messages with the latest job openings
that match your specialty, as well as preferred geographic region,
practice setting, call schedule, and more. Visit the NEJM CareerCenter
at nejmjobs.org for more information.

184 n engl j med 384;2  nejm.org  January 14, 2021

The New England Journal of Medicine

Downloaded from nejm.org at MONASH UNIVERSITY LIBRARY on February 14, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.