biostudies-literaturePeruzzotti-Jametti LItalian Ministry of HealthAustrian Science Fund FWFInstituto de Salud Carlos IIIUniversity of Milano-BicoccaNational Multiple Sclerosis SocietyItalian Ministry of University and ResearchAdelson Medical Research FoundationMedical Research CouncilUK Regenerative Medicine PlatformAISMMultiple Sclerosis SocietyWellcome Trust3505-3513https://www.ebi.ac.uk/biostudies/studies/S-EPMC12493045biostudies-literatureUnknown148(10)The limited ability of CNS progenitor cells to differentiate into oligodendrocytes limits the repair of demyelinating lesions and contributes to the disability of people with progressive multiple sclerosis (PMS). Neural stem cell (NSC) transplantation has emerged as a safe therapeutic approach in people with PMS, where it holds the promise of healing the injured CNS. However, the mechanisms by which NSC grafts could promote CNS remyelination need to be carefully assessed before their widespread clinical adoption. In this study, we used directly induced NSCs (iNSCs) as a novel transplantation source to boost remyelination in the CNS. Using a mouse model of focal lysophosphatidylcholine (LPC)-induced demyelination, we found that mouse iNSCs promote remyelination by enhancing endogenous oligodendrocyte progenitor cells differentiation and by directly differentiating into mature oligodendrocytes. Transplantation of mouse iNSCs in LPC-lesioned Olig1-/- mice, which exhibits impaired remyelination, confirmed the direct remyelinating ability of grafts and the formation of new exogenous myelin sheaths. We also demonstrated that the xenotransplantation of human iNSCs (hiNSCs) is safe in mice, with hiNSCs persisting long-term in demyelinating lesions where they can produce graft-derived human myelin. Our findings support the use of NSC therapies to enhance remyelination in chronic demyelinating disorders, such as PMS.Brain : a journal of neurologyRemyelination of chronic demyelinated lesions with directly induced neural stem cells.PMC12493045PI23/010372014/PMS/4G118541MR/K026666/1RFA-2203-39318203151/Z/16/ZRG79423CB06/05/1131G104956RD24/0014/0009FG-2008-36954CIPROM/2023/053JR20/00033MR/K026682/1G105713Peruzzotti-Jametti LGil-Perotin SBergholt MSKrzak GZhao CBraga ASaeb-Parsy KVolpe GPluchino SVicario ND'Amico GWillis CMStevens MMLombardi IGarcia-Verdugo JMKwok CBarea-Moya LNicaise AMRizzi SFranklin RJMHruba OEdenhofer FD'Angelo AfalseRemyelination of chronic demyelinated lesions with directly induced neural stem cells.The limited ability of CNS progenitor cells to differentiate into oligodendrocytes limits the repair of demyelinating lesions and contributes to the disability of people with progressive multiple sclerosis (PMS). Neural stem cell (NSC) transplantation has emerged as a safe therapeutic approach in people with PMS, where it holds the promise of healing the injured CNS. However, the mechanisms by which NSC grafts could promote CNS remyelination need to be carefully assessed before their widespread clinical adoption. In this study, we used directly induced NSCs (iNSCs) as a novel transplantation source to boost remyelination in the CNS. Using a mouse model of focal lysophosphatidylcholine (LPC)-induced demyelination, we found that mouse iNSCs promote remyelination by enhancing endogenous oligodendrocyte progenitor cells differentiation and by directly differentiating into mature oligodendrocytes. Transplantation of mouse iNSCs in LPC-lesioned Olig1-/- mice, which exhibits impaired remyelination, confirmed the direct remyelinating ability of grafts and the formation of new exogenous myelin sheaths. We also demonstrated that the xenotransplantation of human iNSCs (hiNSCs) is safe in mice, with hiNSCs persisting long-term in demyelinating lesions where they can produce graft-derived human myelin. Our findings support the use of NSC therapies to enhance remyelination in chronic demyelinating disorders, such as PMS.2025-01-01T00:00:00Z2025 Oct2026-06-04T05:41:36.985Z2026-06-04T03:06:23.173ZS-EPMC124930454062227210.1093/brain/awaf208