Single-Cell Transcriptomic Insights into Conserved and Divergent Oligodendrocyte Lineage Programs Across Species

Oligodendrocyte lineage cells (OLLCs) are essential for myelination and neural support, yet how their transcriptional programs are conserved or diverge across species remains unclear. We analyzed around one million hippocampal single-cell and single-nucleus transcriptomes from humans, cynomolgus macaques, rhesus macaques, and mice. OLLCs exhibited high transcriptional conservation, with precursor subtypes preserved but oligodendrocytes showing species-specific diversity. We identified primate-specific regulators such as CNDP1 and temporally shifted ETV1 expression, which were validated by immunofluorescence staining and qRT-PCR. Disease module analysis showed OLLCs provide a conserved substrate for brain aging and neurological disorders, with rhesus macaques displaying greater concordance with humans than cynomolgus macaques or mice. Analysis of OLLC aging trajectories identified primate-specific activation of Wnt pathways in oligodendrocyte precursor cell, contrasting with ribosomal enrichment in mice. These findings define conserved and divergent OLLC programs and underscore nonhuman primates—particularly rhesus macaques—as highly relevant translational models for human myelin biology.