@article{ded2c04d8b4640799797b5c2fc1cf50a,
title = "Versican promotes T helper 17 cytotoxic inflammation and impedes oligodendrocyte precursor cell remyelination",
abstract = "Remyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition of inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation to exacerbate injury is unknown. Here, we correlate high versican-V1 expression in MS lesions with deficient premyelinating oligodendrocytes, and highlight its selective upregulation amongst CSPG members in experimental autoimmune encephalomyelitis (EAE) lesions modeling MS. In culture, purified versican-V1 inhibits oligodendrocyte precursor cells (OPCs) and promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 cells are particularly toxic to OPCs. In NG2CreER:MAPTmGFP mice illuminating newly formed GFP+ oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment from peak EAE reduces lesional versican-V1 and Th17 frequency, while enhancing GFP+ profiles. We suggest that lesion-elevated versican-V1 directly impedes OPCs while it indirectly inhibits remyelination through elevating local Th17 cytotoxic neuroinflammation. We propose CSPG-lowering drugs as potential dual pronged repair and immunomodulatory therapeutics for MS.",
author = "Samira Ghorbani and Emily Jelinek and Rajiv Jain and Benjamin Buehner and Cenxiao Li and Lozinski, {Brian M.} and Susobhan Sarkar and Kaushik, {Deepak K.} and Yifei Dong and Wight, {Thomas N.} and Soheila Karimi-Abdolrezaee and Schenk, {Geert J.} and Strijbis, {Eva M.} and Jeroen Geurts and Ping Zhang and Chang-Chun Ling and Yong, {V. Wee}",
note = "Funding Information: We thank the Hotchkiss Brain Institute Advanced Microscopy Platform facility for microscopy and image analysis platforms. We thank the UK Multiple Sclerosis and Parkinson{\textquoteright}s Tissue Bank at Imperial College, London, and Dr. Djordje Gveric for the tissues in Fig. . We thank Dr. Alex Prat (University of Montreal) for the samples in Supplementary Fig. . This work was funded by operating grants from the Multiple Sclerosis Society of Canada (MSSC) and Canadian Institutes of Health Research (CIHR) to VWY (grant number 3527 and FDN 167270, respectively). SG acknowledges postdoctoral fellowship support from the Harley N. Hotchkiss Postdoctoral Fellowship, MSSC and CIHR. R.J. and D.K.K. acknowledge postdoctoral fellowship support from MSSC. B.L. gratefully acknowledges studentships from the Alberta Graduate Excellence Scholarship and MSSC. V.W.Y. acknowledges salary support from the Canada Research Chair (Tier 1) program. Funding Information: We thank the Hotchkiss Brain Institute Advanced Microscopy Platform facility for microscopy and image analysis platforms. We thank the UK Multiple Sclerosis and Parkinson{\textquoteright}s Tissue Bank at Imperial College, London, and Dr. Djordje Gveric for the tissues in Fig. 1a, b. We thank Dr. Alex Prat (University of Montreal) for the samples in Supplementary Fig. 1. This work was funded by operating grants from the Multiple Sclerosis Society of Canada (MSSC) and Canadian Institutes of Health Research (CIHR) to VWY (grant number 3527 and FDN 167270, respectively). SG acknowledges postdoctoral fellowship support from the Harley N. Hotchkiss Postdoctoral Fellowship, MSSC and CIHR. R.J. and D.K.K. acknowledge postdoctoral fellowship support from MSSC. B.L. gratefully acknowledges studentships from the Alberta Graduate Excellence Scholarship and MSSC. V.W.Y. acknowledges salary support from the Canada Research Chair (Tier 1) program. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
day = "1",
doi = "https://doi.org/10.1038/s41467-022-30032-0",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}