SOX10 Overexpression Enhances the Oligodendrocyte Lineage Commitment of iOPCs In Vitro by Reshaping Their Chromatin Binding Landscape

Although transplantation of induced oligodendrocyte progenitor cells (iOPCs) is a promising strategy for white matter injury, the therapeutic efficacy of in vitro-generated iOPCs remains limited due to insufficient differentiation potential. Here, we aimed to identify key transcription factors and small-molecule drugs to optimize iOPC quality. Through transcriptome sequencing and bioinformatics analysis, we identified the transcription factor SOX10, which is differentially expressed between endogenous fetal OPCs and exogenous iOPCs. We established lentivirus-mediated SOX10 overexpression in neural stem cells (NSCs) before iOPC induction and performed cellular assays and multi-omics analysis. Early SOX10 overexpression reduced cell migration but promoted maturation into oligodendrocytes and suppressed astrocyte differentiation. Multi-omics analyses revealed that SOX10 overexpression is associated with the extensive redistribution of SOX10 chromatin binding and enrichment of regulatory programs linked to oligodendroglial differentiation, including the activation of the key signaling downstream transcription factors JUN/FOS. Moreover, TSA, Dabrafenib, and Fedratinib effectively upregulated SOX10 and improved iOPC differentiation. This study identifies SOX10 as a core upstream regulator governing the fate of iOPCs, providing a potential strategy for optimizing iOPC induction for future investigation of white matter injury therapy.