Chronic demyelination of rabbit lesions is attributable to failed oligodendrocyte progenitor cell repopulation

Abstract

The failure of remyelination in the human CNS contributes to axonal injury and disease progression in multiple sclerosis (MS). In contrast to regions of chronic demyelination in the human brain, remyelination in murine models is preceded by abundant oligodendrocyte progenitor cell (OPC) repopulation, such that OPC density within regions of demyelination far exceeds that of normal white matter (NWM). As such, we hypothesized that efficient OPC repopulation was a prerequisite of successful remyelination, and that increased lesion volume may contribute to the failure of OPC repopulation in human brain. In this study, we characterized the pattern of OPC activation and proliferation following induction of lysolecithin-induced chronic demyelination in adult rabbits. The density of OPCs never exceeded that of NWM and oligodendrocyte density did not recover even at 6 months post-injection. Rabbit OPC recruitment in large lesions was further characterized by chronic Sox2 expression in OPCs located in the lesion core and upregulation of quiescence-associated Prrx1 mRNA at the lesion border. Surprisingly, when small rabbit lesions of equivalent size to mouse were induced, they too exhibited reduced OPC repopulation. However, small lesions were distinct from large lesions as they displayed an almost complete lack of OPC proliferation following demyelination. These differences in the response to demyelination suggest that both volume dependent and species-specific mechanisms are critical in the regulation of OPC proliferation and lesion repopulation and suggest that alternate models will be necessary to fully understand the mechanisms that contribute to failed remyelination in MS. [Abstract copyright: © 2022 Wiley Periodicals LLC.]

Publication DOI: https://doi.org/10.1002/glia.24324
Divisions: College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences > Aston Medical School > Translational Medicine Research Group (TMRG)
Additional Information: Copyright © 2022, Wiley Periodicals LLC. This is the peer reviewed version of the following article: '"J.J.M. Cooper et al (2022). "Chronic demyelination of rabbit lesions is attributable to failed oligodendrocyte progenitor cell repopulation". Glia,' which has been published in final form at [https://doi.org/10.1002/glia.24324]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. Funding Information: This work was supported by the Department of Defense CongressionallyDirected Medical Research Programs (W81XWH-21-1-0387), NINDSgrant (R01NS104021), National Multiple Sclerosis Society (RG-1701-26750 and PP-1706-28080), the Kalec Multiple Sclerosis Founda-tion, and the Change MS Foundation. JJP received additional supportfrom NIGMS (R25GM09545902), NCATS (UL1TR001412-S1), and New York State Department of Health (Empire State Stem Cell Fund) through the Stem Cells in Regenerative Medicine Fellowship (NYSTEMC30290GG). The authors acknowledge support provided by the Center for Computational Research at the University at Buffalo for use of the academiccompute cluster for training the Keras-based convolution network.
Uncontrolled Keywords: remyelination,multiple sclerosis,models,CNS myelin,oligodendrocyte
Publication ISSN: 1098-1136
Last Modified: 14 Jun 2024 07:27
Date Deposited: 18 Jan 2023 10:29
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://onlinel ... 1002/glia.24324 (Publisher URL)
PURE Output Type: Article
Published Date: 2022-12-20
Published Online Date: 2022-12-20
Accepted Date: 2022-12-07
Submitted Date: 2022-08-18
Authors: Cooper, James J M
Polanco, Jessie J
Saraswat, Darpan
Peirick, Jennifer J
Seidl, Anna
Li, Yi
Ma, Dan (ORCID Profile 0000-0001-8628-8954)
Sim, Fraser J

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