Stem Cell-Based Therapies for Central Nervous System Demyelinating Diseases: Clinical Evidence, Therapeutic Niches, and Translational Boundaries.

Central nervous system demyelinating disorders differ substantially in pathobiology, reversibility, and capacity for tissue repair. Disease-modifying therapies can suppress inflammatory activity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), but they do not replace lost oligodendrocytes or reliably reverse established neuroaxonal injury. Stem cell-based strategies therefore pursue distinct therapeutic goals, including immune reconstitution, paracrine immunomodulation and neuroprotection, direct cell replacement, remyelination, and correction of defined genetic defects. Autologous hematopoietic stem cell transplantation (AHSCT) currently has the most mature clinical evidence, particularly for carefully selected patients with highly active relapsing MS despite high-efficacy therapy, but its benefit is mediated primarily through immune ablation and reconstitution rather than direct remyelination. Mesenchymal stromal cell (MSC) approaches remain investigational because controlled trials have not established consistent efficacy and intrathecal delivery has raised route-specific safety concerns. MSC-derived extracellular vesicles and induced pluripotent stem cell (iPSC)-derived oligodendrocyte or neural progenitor products remain preclinical or early translational approaches for acquired demyelinating disease, whereas gene-modified hematopoietic stem cells have a distinct role in selected inherited leukodystrophies. Translation across these platforms is additionally constrained by product heterogeneity, potency assessment, manufacturing reproducibility, long-term safety, regulation, scalability, access, and the need for mechanism-matched clinical endpoints. This article aims to critically review the clinical evidence, therapeutic niches, safety considerations, and translational boundaries of stem cell-based therapies for central nervous system demyelinating diseases, with particular emphasis on MS and NMOSD.