INSIGHTS | PERSPECTIVESsciencemag.org SCIENCEGRAPHIC: KELLIE HOLOSKI/SCIENCEREGENERATIONCoaxing stem cells to repair the spinal cord
Spinal cells in mice can be induced to generate protective oligodendrocytes after injury
By Catherina G. Becker and Thomas BeckerS
pinal cord injuries destroy neurons, ax-
onal processes, and oligodendrocytes
that provide insulation and protection
of axons by means of membrane wrap-
pings, called myelin sheaths. None of
these cellular structures are efficiently
replaced after injury. This can lead to lifelong
disabilities, including paralysis. Endogenous
stem cells exist in the spinal cord, but after
injury they produce mainly astrocytic scar
tissue, no neurons, and very few oligoden-
drocytes ( 1 ). On page 73 of this issue, Llorens-
Bobadilla et al. ( 2 ) show that by overexpress-
ing a single factor in spinal stem cells, they
can boost post-injury production of oligoden-
drocytes in mice. This leads to better remy-
elination of remaining axons that lost their
myelin and to improved axonal impulse con-
duction in vivo. The study raises hope that
endogenous stem cells in the injured spinal
cord can be recruited to generate neural cell
types in a more balanced way after injury to
promote recovery of function.
One of the problems with spinal cord in-
jury is secondary cell death around an injury
site that leads to the loss of not only neurons,
but also oligodendrocytes and the myelin
sheaths they produce. This in turn causes de-
nuding of spared axons, which, bereft of their
insulation and trophic support, function
inefficiently and may ultimately degener-
ate. Llorens-Bobadilla et al. analyzed mouse
ependymal cells (stem cells in the lining of
the spinal cord central canal) to find that
chromatin regions with binding motifs for
the oligodendrocyte-determining transcrip-
tion factors OLIG2 (oligodendrocyte tran-
scription factor 2) and SOX10 were accessible
even though the transcription factors were
not expressed. This suggested a latent capac-
ity of ependymal cells to generate oligoden-
drocytes. Indeed, inducing overexpression
of OLIG2 in ependymal cells in vivo strongly
increased the accessibility of OLIG2 binding
sites and the production of oligodendrocytes
from these cells after spinal injury.
Neither promoter accessibility nor oligo-
dendrocyte production increased without an
injury, indicating that factors in addition to
OLIG2 expression are necessary to realize the
latent potential of ependymal cells for oligo-dendrocyte production. Injury induces ep-
endymal cells to proliferate, which changes
gene accessibility. Moreover, spinal injury
induces inflammation ( 3 ) and attendant sig-
naling molecules that may influence gene ex-
pression in ependymal cells, but these factors
are largely unknown.
The observed increase in oligodendrocyte
numbers was substantial. High numbers
of cells may have been reached because the
progeny of ependymal cells comprises prolif-
erative oligodendrocyte progenitors that can
be considered transit-amplifying cells for oli-
godendrocytes. Even though oligodendrocyte
production was boosted from less than 1% tomore than one-third of ependymal progeny,
the astrocytic scar, which also consists of
cells derived from ependymal cells, was not
depleted. The astrocytic scar has protective
functions in wound healing ( 4 ), so it is im-
portant that any therapeutic approach does
not compromise scar tissue. Together, these
findings indicate that ependymal cells in the
spinal cord can be reprogrammed for oligo-
dendrocyte production after injury in mice.
Full differentiation of oligodendrocytes is
a prerequisite for efficient impulse propaga-
tion in axons. One problem with naturally
occurring remyelination is that new my-
elin sheaths are usually thinner than those
that were originally present, compromising
conduction velocity. It will be interesting to
find out whether new myelin displays “full
thickness” and is comparable to myelin
that has arisen during development. It will
also be interesting to determine whether
new myelin persists for longer than the 3
months reported in this study to indicate
permanent repair.
Llorens-Bobadilla et al. found that induced
myelin improved conductance velocity in
a mouse model of spinal cord injury. The
model is a contusion injury, which resembles
the physical impact associated with injuries
in humans. Conductance velocity in spared
axons above the injury site was improved
in OLIG2-overexpressing animals compared
to injured controls, ostensibly because of
improved myelination. Below the injury, no
such effects were observed, likely because of
the scarcity of spared axons. Consequently,
recovery of function was not better in OLIG2-
overexpressing animals.
To bring about functional recovery, com-
binations with other treatments would be
needed ( 5 ) because although oligodendro-
cytes can support axons, remyelination alone
is insufficient to boost recovery ( 6 ). For exam-
ple, axon growth can be enhanced by modu-
lating intrinsic axon growth propensity ( 7 )
or the inhibitory environment ( 8 ). Moreover,
transplanted neural stem cells can form new
neurons that integrate and improve neuronal
impulse conduction over an injury site ( 9 ).
Electrical stimulation of spared fibers may
also lead to more efficient myelination ( 10 ).
In all approaches, newly grown axons could
benefit from additional myelination capacity
from induced oligodendrocytes.
To realize the potential of ependymal cells
in human spinal cord injuries, it will be nec-Preexisting
oligodendrocyteNew
oligodendrocyteDestroyed
myelinCompression
injuryOLIG2Spinal cord
Ependymal
cellsCorticospinal
neuronsUniversity of Edinburgh, Edinburgh, Scotland, UK. Email:
[email protected]; [email protected]36 2 OCTOBER 2020 • VOL 370 ISSUE 6512Induced protection
Chromatin in adult ependymal cells in the mouse spinal
cord is accessible to the transcription factor OLIG2
(oligodendrocyte transcription factor 2). After spinal
cord injury, myelin is lost near the injury site and can
be lost from spared axons. Overexpression of OLIG2 in
ependymal cells in mice reprograms these stem cells
to produce more oligodendrocytes, which form new
myelin near the injury and improve axon conduction.