Astrocytic TIMP-1 regulates production of Anastellin, an inhibitor of oligodendrocyte differentiation and FTY720 responses

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. Astrocytes that lack expression of do not support rat oligode...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2024-01, Vol.121 (5), p.e2306816121-e2306816121
Main Authors: Sutter, Pearl A, Willis, Cory M, Menoret, Antoine, Nicaise, Alexandra M, Sacino, Anthony, Sikkema, Arend H, Jellison, Evan R, Win, Kyaw K, Han, David K, Church, William, Baron, Wia, Vella, Anthony T, Crocker, Stephen J
Format: Article
Language:English
Subjects:
Animals
Astrocytes
Cell differentiation
Cells (biology)
Cerebrospinal fluid
Demyelination
Differentiation
Experimental allergic encephalomyelitis
Fibronectin
Fibronectins - genetics
Fingolimod Hydrochloride - pharmacology
FTY720
Glial stem cells
Growth factors
Injury analysis
Metalloproteinase
Mice
Mice, Inbred C57BL
Multiple sclerosis
Multiple Sclerosis - drug therapy
Myelination
Peptide Fragments
Peptides
Progenitor cells
Protease inhibitors
Proteinase inhibitors
Proteomics
Rats
Secretome
Sphingosine 1-phosphate
Tissue inhibitor of metalloproteinase 1
Tissue Inhibitor of Metalloproteinase-1 - genetics
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Summary:Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. Astrocytes that lack expression of do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global knockout ( ) mice do not efficiently remyelinate following a demyelinating injury. Here, we performed an unbiased proteomic analysis and identified a fibronectin-derived peptide called Anastellin (Ana) that was unique to the astrocyte secretome. Ana was found to block rOPC differentiation in vitro and enhanced the inhibitory influence of fibronectin on rOPC differentiation. Ana is known to act upon the sphingosine-1-phosphate receptor 1, and we determined that Ana also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiation Administration of FTY720 to wild-type C57BL/6 mice during MOG -experimental autoimmune encephalomyelitis ameliorated clinical disability while FTY720 administered to mice lacking expression of ( ) had no effect. Analysis of and fibronectin ( ) transcripts from primary human astrocytes from healthy and multiple sclerosis (MS) donors revealed lower expression was coincident with elevated in MS astrocytes. Last, analyses of proteomic databases of MS samples identified Ana peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high disease activity. A role for Ana in MS as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and innate remyelination potential in the MS brain.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2306816121