Single-cell transcriptomic insights into conserved and divergent oligodendrocyte lineage programs across species

Oligodendrocyte lineage cells (OLLCs) are essential for myelination and neuronal homeostasis, yet the evolutionary conservation of their transcriptional programs remains unclear. Here, we integrated approximately one million hippocampal single-cell and single-nucleus transcriptomes from humans, rhesus macaques, cynomolgus macaques, and mice. OLLCs emerged as among the most evolutionarily conserved neural cell populations, with oligodendrocyte precursor cells exhibiting highly conserved transcriptional identities, whereas mature oligodendrocytes displayed greater species-specific diversification We identified evolutionarily divergent genes, including the primate-specific gene CNDP1, and uncovered a species-specific temporal shift of the transcription factor ETV1 during oligodendrocyte differentiation. Cross-species analysis of aging revealed conserved chromatin-regulatory programs together with species-specific aging signatures, including coordinated remodeling of a primate-specific Wnt regulatory network in primate OPCs, whereas aged mouse OPCs were enriched for ribosome biogenesis. Disease-risk signatures further underscore the involvement of OLLCs in neurological disorders. Together, these findings provide a comparative framework for understanding mammalian myelin biology, brain aging, and disease.