Neural Stem Cells in Demyelinating Diseases: Interplay Between Lineage Potential and the Microenvironmental Constraints in Remyelination

ABSTRACT Failure of remyelination is a major determinant of progressive neurological decline in demyelinating disorders of the central nervous system. Although endogenous repair mechanisms are activated following injury, the generation of fully functional myelinating oligodendrocytes is frequently insufficient to restore long‐term tissue integrity. In addition to oligodendrocyte progenitor cells, neural stem cells (NSCs) residing in adult neurogenic niches represent a potential endogenous source of oligodendroglial regeneration. However, promoting effective remyelination from NSCs requires more than stimulating lineage commitment, as progenitor fate and maturation are tightly regulated by lesion‐specific microenvironmental cues. Over the past decades, a wide range of experimental models—including reductionist in vitro systems, organoid platforms, toxin‐induced or immune‐mediated demyelination in vivo models—have provided important mechanistic insights into NSCs activation and oligodendroglial differentiation. Yet, no single model fully captures the complexity of chronic human pathology, highlighting significant translational limitations. Moreover, inflammatory signaling, glial reactivity, and extracellular matrix remodeling critically influence whether enhanced oligodendrogenesis results in effective remyelination. In this review, we analyze current experimental frameworks used to investigate NSCs‐driven oligodendrogenesis and discuss how microenvironmental regulation shapes regenerative outcomes. We further examine emerging therapeutic strategies aimed at modulating endogenous NSCs and their niche, including pharmacological approaches, cell‐based interventions, and nanotechnology‐based platforms. By integrating experimental and translational perspectives, we propose that successful remyelination requires coordinated modulation of both progenitor competence and lesion microenvironment. image