Science - USA (2020-10-02)

RESEARCH ARTICLE SUMMARY

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NEURODEVELOPMENT

A latent lineage potential in resident neural stem

cells enables spinal cord repair

Enric Llorens-Bobadilla, James M. Chell, Pierre Le Merre, Yicheng Wu, Margherita Zamboni,
Joseph Bergenstråhle, Moa Stenudd, Elena Sopova, Joakim Lundeberg, Oleg Shupliakov,
Marie Carlén, Jonas Frisén*

INTRODUCTION:The capacity of a tissue to re-
generate itself rests on the potential of its
resident cells to replace cells lost to injury.
Some tissues, such as skin or intestine, do
this remarkably well through the activation
of tissue-specific stem cells. Injuries to the
central nervous system (CNS), in contrast,
often lead to permanent functional impair-
ment; some cells lost to injury are never re-
placed. Neural stem cells have been identified
intheadultbrainandspinalcordandare
activated by injury. However, injury-activated
neural stem cells predominantly produce scar-
forming astrocytes, and the contribution of
neural stem cells to cell replacement is insuf-
ficient for regeneration. To design regener-
ative strategies aimed at recruiting resident
neural stem cells for repair, it is essential to
know whether greater regenerative potential
exists and how to elicit such potential.

RATIONALE:The spinal cord is a great system to

study neural stem cell recruitment for repair.

The neural stem cell potential of the spinal

cord resides in a well-characterized popula-

tion of ependymal cells. Ependymal cells, nor-

mally quiescent, are activated by injury to

generate almost exclusively scar-forming as-

trocytes. Ependymal-derived astrocytes help

to preserve tissue integrity, but other cell types,

such as myelin-forming oligodendrocytes, are

insufficiently replaced. In parallel, neural stem

cell transplantation has proven to be beneficial

to recovery after spinal cord injury—a benefit

that is associated with the increased supply of

oligodendrocytes able to remyelinate demye-

linated axons. Ependymal cells share a devel-

opmental origin with spinal oligodendrocytes,

which led us to explore whether a latent po-

tential for expanded oligodendrocyte gener-

ation might exist.

RESULTS:We integrated single-cell RNA se-

quencing (scRNA-seq) and single-cell assay

for transposase-accessible chromatin using

sequencing (scATAC-seq) to study lineage po-

tential in adult ependymal cells of the mouse

spinal cord. We found that the genetic program

for oligodendrocyte generation is accessible

in ependymal cells. However, this program is

latent, as oligodendrocyte genes are not ex-

pressed. In particular, we found that a large

fraction of binding sites for OLIG2, the tran-

scription factor that initiates developmental

oligodendrogenesis, had basal accessibility,

despite OLIG2 and its key target genes not

being expressed in adult ependymal cells. To

study whether this latent accessibility was

associated with a greater capacity to produce

oligodendrocytes, we genetically engineered

a mouse model to express OLIG2 in adult epen-

dymal cells. We found that OLIG2 expression was

compatible with ependymal identity during

homeostasis. However, after injury, OLIG2 ex-

pression led to the increased accessibility of

the latent program and subsequent expression

of genes specifying oligodendrocyte identity.

Unfolding of the latent program was followed

by efficient oligodendrocyte production from

ependymal cells, but not from astrocytes, after

injury. Using scRNA-seq of ependymal-derived

cells, we found that new oligodendrocytes fol-

lowed the developmental program of oligoden-

drocyte maturation, including a self-amplifying

oligodendrocyte progenitor cell–like state. These

cells later matured to acquire the identity of

resident mature myelinating oligodendrocytes.

Further, ependymal oligodendrocyte genera-

tion occurred in parallel and not at the ex-

pense of astrocyte scarring. Newly recruited

ependymal-derived oligodendrocytes migrated

to sites of demyelination, where they remyeli-

nated axons over the long term. Finally, using

optogenetics, we found that ependymal-derived

oligodendrocytes contributed to normalizing

axon conduction after injury.

CONCLUSION:Adult neural stem cells have a

greater potential for regeneration than is nor-

mally manifested. Targeted activation of such

potential leads to the recruitment of neural

stem cells for the generation of remyelinat-

ing oligodendrocytes in numbers comparable

to those obtained via cell transplantation.

Resident stem cells can thus serve as a re-

servoir for cellular replacement and may offer

an alternative to cell transplantation after

CNS injury.▪

RESEARCH

SCIENCEsciencemag.org 2 OCTOBER 2020•VOL 370 ISSUE 6512 73

The list of author affiliations is available in the full article online.

*Corresponding author. Email: [email protected]

Cite this article as E. Llorens-Bobadillaet al.,Science 370 ,

eabb8795 (2020). DOI: 10.1126/science.abb8795

READ THE FULL ARTICLE AT

https://doi.org/10.1126/science.abb8795

Myelinated

axon

Demyelinated

axon

Ependymal-derived

oligodendrocyte

Oligodendrocyte

Latent accessibility of

oligodendrocyte genes in ependymal cells

Injured

Ependymal

cell

Enhanced

injury repair

+ Olig2

Ependymal-derived

scar astrocyte

Integration of single-cell RNA-seq and

ATAC-seq from the mouse spinal cord

Latent potential in neural stem cells.Through the integration of different layers of genomic information in
single cells, we found that the genetic program for oligodendrocyte generation is latently accessible in
ependymal neural stem cells of the adult spinal cord. After injury, activating the latent potential by forced
OLIG2 expression unfolds efficient oligodendrocyte generation, leading to enhanced repair.