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Title: | Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination | Authors: | HOUBEN, Evelien JANSSENS, Kris HERMANS, Doryssa Vandooren, Jennifer Van den Haute, Chris SCHEPERS, Melissa VANMIERLO, Tim LAMBRICHTS, Ivo VAN HORSSEN, Jack Baekelandt, Veerle OPDENAKKER, Ghislain Baron, Wia BROUX, Bieke Slaets, Helena HELLINGS, Niels |
Issue Date: | 2020 | Publisher: | NATL ACAD SCIENCES | Source: | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF, AMERICA, 117 (9) , p. 5028 -5038 | Abstract: | The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMR beta knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMR beta KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders. | Notes: | Hellings, N (reprint author), Hasselt Univ, Biomed Res Inst, Dept Immunol, B-3590 Diepenbeek, Belgium. niels.hellings@uhasselt.be |
Other: | Hellings, N (reprint author), Hasselt Univ, Biomed Res Inst, Dept Immunol, B-3590 Diepenbeek, Belgium. niels.hellings@uhasselt.be | Keywords: | oncostatin M;remyelination;oligodendrocyte precursor cells;astrocytes;tissue inhibitor of metalloproteinases-1 | Document URI: | http://hdl.handle.net/1942/30888 | ISSN: | 0027-8424 | e-ISSN: | 1091-6490 | DOI: | 10.1073/pnas.1912910117 | ISI #: | WOS:000518473500077 | Rights: | 2020 National Academy of Sciences. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2021 |
Appears in Collections: | Research publications |
Files in This Item:
File | Description | Size | Format | |
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2020 Houben et al PNAS suppl.pdf | Published version | 827.28 kB | Adobe PDF | View/Open |
2020 Houben et al PNAS.pdf | Published version | 3.17 MB | Adobe PDF | View/Open |
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