Spontaneous differentiation across cell lineages of separate germ layer origin during progenitor cell-mediated regeneration of the central nervous system (in vitro data)

ABSTRACT: Under homeostatic conditions, axons of the central nervous system (CNS) are myelinated by oligodendrocytes. However, in response to demyelination, Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), can contribute to CNS remyelination. Lineage tracing studies demonstrated that many CNS remyelinating SCs, in addition to remyelinating oligodendrocytes, are derived from adult CNS stem cells called oligodendrocyte progenitor cells (OPCs). Here we describe the mechanisms by which the fate switch of neuroepithelial-derived OPCs into SCs, a cell normally of neural crest origin, occurs. Using single-cell RNA-sequencing we identified a subpopulation of OPCs within demyelinating lesions that co-express SC markers. Within this SC-primed group, differential gene analysis revealed a significant upregulation of genes involved in integrin signalling and bone morphogenetic protein (BMP) activation. We found that BMP4 and vitronectin, an extracellular matrix molecule and integrin ligand, are sufficient external cues to induce SC differentiation by OPCs by directly exerting effects on the transcription factors OLIG2 and SOX10, which are critical regulators of cell fate in oligodendroglial cells and SCs. We also show that OPCs can be directly programmed toward a SC fate by suppressing the expression levels of Olig2 and while maintaining those of Sox10. OPC-derived SCs morphologically and transcriptionally resemble primary SCs and can myelinate CNS axons with peripheral type myelin. Our findings indicate that injury-related changes in the environment destabilise oligodendroglial transcription factor networks, which enable alternative OPC fate choices during CNS remyelination.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE312112 | GEO | 2026/09/24

REPOSITORIES: GEO