Abstract / Summary
Abstract Multiple sclerosis (MS) is a debilitating demyelinating disease of the central nervous system (CNS) in which progressive neurological disability is closely linked to the failure of endogenous remyelination. Reactive astrocytes are hallmarks of MS lesions, yet their functional role in myelin repair remains incompletely understood. Here, we report a pro-regenerative role for reactive astrocytes and demonstrate that their sustained activation during the remyelination phase is essential for oligodendrocyte (OL) precursor cell (OPC) differentiation and myelin repair in a cuprizone (CPZ)-induced demyelination mouse model. Reanalysis of a single-cell transcriptomic atlas combined with in situ immunostaining further revealed the selective upregulation of chemokine C-X-C motif ligand 14 (CXCL14) in reactive astrocytes during remyelination—a finding corroborated in lysolecithin (LPC) mouse model and experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory demyelination model. In vitro, CXCL14 directly drives OPC differentiation into mature OLs by activating the extracellular signal-regulated kinases 1 and 2 (ERK1/2)-mediated mitogen-activated protein kinase (MAPK) signaling pathway, which is independent of its effects on OPC survival or proliferation. Notably, astrocyte‑specific Cxcl14 knockdown abolished the pro‑differentiation activity of reactive astrocyte‑conditioned medium (ACM) in vitro and concurrently impaired remyelination in both the CPZ mouse model and EAE. Our findings reveal novel astrocyte–OPC crosstalk in pro-remyelination driven by CXCL14-dependent ERK1/2 signaling, highlighting CXCL14 as a promising therapeutic target for demyelinating diseases such as MS.