Oligodendrocyte progenitor cells can cross germ-layer boundaries to differentiate into myelinating Schwann cells through a conserved mechanism in which vitronectin and BMP4 signaling stabilize SOX10 while suppressing OLIG2, and direct manipulation of this SOX10/OLIG2 transcriptional circuit enables Schwann cells to overcome astrocytic exclusion and achieve functional remyelination within the injured CNS.

During CNS regeneration, neuroepithelial-derived oligodendrocyte progenitor cells (OPCs) can cross germ-layer boundaries to generate neural-crest-derived Schwann cells (SCs). However, the underlying mechanism and disease relevance of this unique phenomenon of cellular plasticity is unclear. Here, we combine single cell genomics in rodent models of CNS injury and samples from multiple sclerosis patients to characterise OPC-derived SCs. We discover that integrin signalling and bone morphogenetic protein (BMP) activation activate a core SOX10/OLIG2 transcriptional circuit to drive OPC-to-SC differentiation. We show that OPC-derived SCs myelinate in vitro and in vivo, and unlike peripheral SCs, can integrate into astrocyte-rich territories. Together, these findings define a conserved molecular mechanism of adult plasticity, enabling the control of OPC fate choices beyond their germ layer origin for CNS repair.