Brain matters: unveiling the distinct contributions of region, age, and sex to glia diversity and CNS function

Acta Neuropathologica Communications

Research

Neil C. Henderson¹  Justyna Cholewa-Waclaw²  Anna Williams²  Nina-Lydia Kazakou²  Alastair M. Kilpatrick²  Nadine Bestard-Cuche²  Laura J. Wagstaff²  Sunniva M. K. Bøstrand²  Luise A. Seeker²  Sarah Jäkel³  David Van Bruggen⁴  Mukund Kabbe⁴  Fabio Baldivia Pohl⁴  Goncalo Castelo-Branco⁵  Gioele La Manno⁶  Zahra Moslehi⁶  Catalina A. Vallejos⁷ 

[1]Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, UK

[2]MRC Human Genetics Unit, Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, EH4 2XU, Edinburgh, UK

[3]Centre for Regenerative Medicine, Institute for Regeneration and Repair, Edinburgh Bioquarter, University of Edinburgh, 5 Little France Drive, EH16 4UU, Edinburgh, UK

[4]Centre for Regenerative Medicine, Institute for Regeneration and Repair, Edinburgh Bioquarter, University of Edinburgh, 5 Little France Drive, EH16 4UU, Edinburgh, UK

[5]Institute for Stroke and Dementia Research, Klinikum Der Universität München, Ludwig-Maximilians-Universität, Munich, Germany

[6]Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

[7]Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden

[8]Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden

[9]Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Stockholm Node, 171 77, Stockholm, Sweden

[10]Laboratory of Neurodevelopmental Systems Biology, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland

[11]MRC Human Genetics Unit, Institute of Genetics and Cancer, Western General Hospital, University of Edinburgh, EH4 2XU, Edinburgh, UK

[12]The Alan Turing Institute, 96 Euston Road, NW1 2DB, London, UK

关键词: Human glia;    Developmental origin;    Spinal cord;    Ageing;    Myelin;    OPCs;   

DOI  :  10.1186/s40478-023-01568-z

 received in 2023-04-10, accepted in 2023-04-15,  发布年份 2023

来源: Springer

【 摘 要 】

The myelinated white matter tracts of the central nervous system (CNS) are essential for fast transmission of electrical impulses and are often differentially affected in human neurodegenerative diseases across CNS region, age and sex. We hypothesize that this selective vulnerability is underpinned by physiological variation in white matter glia. Using single nucleus RNA sequencing of human post-mortem white matter samples from the brain, cerebellum and spinal cord and subsequent tissue-based validation we found substantial glial heterogeneity with tissue region: we identified region-specific oligodendrocyte precursor cells (OPCs) that retain developmental origin markers into adulthood, distinguishing them from mouse OPCs. Region-specific OPCs give rise to similar oligodendrocyte populations, however spinal cord oligodendrocytes exhibit markers such as SKAP2 which are associated with increased myelin production and we found a spinal cord selective population particularly equipped for producing long and thick myelin sheaths based on the expression of genes/proteins such as HCN2. Spinal cord microglia exhibit a more activated phenotype compared to brain microglia, suggesting that the spinal cord is a more pro-inflammatory environment, a difference that intensifies with age. Astrocyte gene expression correlates strongly with CNS region, however, astrocytes do not show a more activated state with region or age. Across all glia, sex differences are subtle but the consistent increased expression of protein-folding genes in male donors hints at pathways that may contribute to sex differences in disease susceptibility. These findings are essential to consider for understanding selective CNS pathologies and developing tailored therapeutic strategies.

【 授权许可】

CC BY   
© The Author(s) 2023

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Fig. 3