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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:p>In multiple sclerosis (MS), spontaneous remyelination occurs in early disease; however, this process becomes inefficient over time, resulting in sustained neurodegeneration and clinical deterioration. It is known that global tumor necrosis factor receptor 2 (TNFR2) deletion in experimental autoimmune encephalomyelitis (EAE), the murine MS model, causes a severe nonremitting disease; however, the underlying mechanism is poorly understood. Here, through bulk and single nucleus RNA sequencing, we identify endothelial TNFR2 deletion as the driver of nonremitting disease, as it is sufficient to drive a severe nonremitting phenotype that closely mirrors global TNFR2 loss. Remyelination failure upon endothelial cell\u2013specific TNFR2 ablation was also detected at the Cuprizone model of remyelination confirming its dominant role in central nervous system (CNS) repair. Notably, this effect was independent of immune cell influx or vascular permeability changes but associated with fibronectin overexpression and accumulation in demyelinating lesions. Fibronectin accumulation led to the sequestering of oligodendrocyte progenitor cells (OPCs) at the demyelination areas and prevented myelin repair. Therapeutically, systemic fibronectin inhibition restored regeneration and clinical remission, as well as prevented OPC accumulation at lesions, providing strong preclinical evidence for fibronectin-targeting therapies in MS and other demyelinating disorders. These findings establish endothelial cells as key regulators of the parenchymal environment permissive to remyelination and open avenues for MS treatment strategies focused on vascular-driven CNS regeneration.<\/jats:p>","DOI":"10.1073\/pnas.2616799123","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:47:37Z","timestamp":1788889657000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Fibronectin inhibition restores myelination in endothelial TNFR2\u2013dependent nonremitting experimental autoimmune encephalomyelitis"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6971-2661","authenticated-orcid":false,"given":"Aikaterini","family":"Nanou","sequence":"first","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d","place":["Athens, 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