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.

We thank the Institute of Primate Translational Medicine at Kunming University of Science and Technology for providing non-human primate tissue samples from its biobank. This study was supported by the Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project (2022ZD0207700), the National Natural Science Foundation of China (Nos. 82371578, 82060234 and 32260197), the Basic Research Program of Yunnan Province (No. 202301AT070412), the Xingdian Talent Support Program of Yunnan province to Fucheng Luo. These authors contributed equally: Xi Han, Lingyan Zuo.

State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China Xi Han, Lingyan Zuo, Zhen Zhang, Yuanyi Yu, Jinsheng Hu, Qian Long, Xin Tian, Jingkuan Wei, Runrui Zhang & Fucheng Luo Yunnan Key Laboratory of Primate Biomedical Research, Kunming, China Correspondence to Runrui Zhang or Fucheng Luo. The authors declare no competing interest. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material.

If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Han, X., Zuo, L., Zhang, Z. et al.