Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination.
The Sox family of transcription factors have been widely studied in the context of oligodendrocyte development. However, comparatively little is known about the role of Sox2, especially during CNS remyelination. Here we show that the expression of Sox2 occurs in oligodendrocyte progenitor cells (OPCs) in rodent models during myelination and in activated adult OPCs responding to demyelination, and is also detected in multiple sclerosis lesions. In normal adult white matter of both mice and rats, it is neither expressed by adult OPCs nor by oligodendrocytes (although it is expressed by a subpopulation of adult astrocytes). Overexpression of Sox2 in rat OPCs in vitro maintains the cells in a proliferative state and inhibits differentiation, while Sox2 knockout results in decreased OPC proliferation and survival, suggesting that Sox2 contributes to the expansion of OPCs during the recruitment phase of remyelination. Loss of function in cultured mouse OPCs also results in an impaired ability to undergo normal differentiation in response to differentiation signals, suggesting that Sox2 expression in activated OPCs also primes these cells to eventually undergo differentiation. In vivo studies on remyelination following experimental toxin-induced demyelination in mice with inducible loss of Sox2 revealed impaired remyelination, which was largely due to a profound attenuation of OPC recruitment and likely also due to impaired differentiation. Our results reveal a key role of Sox2 expression in OPCs responding to demyelination, enabling them to effectively contribute to remyelination.


CONCLUSIONS
Understanding the mechanisms of CNS remyelination is central to developing effective means by which this process can be therapeutically enhanced in chronic demyelinating diseases such as multiple sclerosis. In this study, we describe the role of Sox2, a transcription factor widely implicated in stem cell biology, in CNS myelination and remyelination. We show how Sox2 is expressed in oligodendrocyte progenitor cells (OPCs) preparing to undergo differentiation, allowing them to undergo proliferation and priming them for subsequent differentiation. Although Sox2 is unlikely to be a direct therapeutic target, these data nevertheless provide more information on how OPC differentiation is controlled and therefore enriches our understanding of this important CNS regenerative process.
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and rjf1000@cam.ac.uk cz213@cam.ac.uk.
Chao
C
Zhao
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and.
Dan
D
Ma
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and.
Malgorzata
M
Zawadzka
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and.
Stephen P J
http://orcid.org/0000-0002-2818-8258
SP
Fancy
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and.
Lowri
L
Elis-Williams
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and.
Guy
http://orcid.org/0000-0002-6160-7186
G
Bouvier
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and.
John H
http://orcid.org/0000-0002-7385-8310
JH
Stockley
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and.
Glaucia Monteiro
GM
de Castro
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and.
Bowei
B
Wang
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and.
Sabrina
S
Jacobs
Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029-6574.
Patrizia
http://orcid.org/0000-0002-4785-9264
P
Casaccia
Wellcome Trust-Medical Research Council Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, United Kingdom, and rjf1000@cam.ac.uk cz213@cam.ac.uk.
Robin J M
RJ
Franklin
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology*; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology*
D055748:SOXB1 Transcription Factors; C527784:Sox2 protein, rat
Sox2; demyelination; oligodendrocyte progenitor cells; remyelination