Brain matters: Unveiling the Distinct Contributions of Region, Age, and Sex to Glia diversity and CNS Function!
Short title: Human glia diversity with CNS region, age and sex
Luise A. Seeker1, Nadine Bestard-Cuche1, Sarah Jaekel1,2,3, Nina-Lydia Kazakou1, Sunniva M. K. Bøstrand1, Laura J. Wagstaff1, Justyna Cholewa-Waclaw1, Alastair M. Kilpatrick1, David Van Bruggen4, Mukund Kabbe4, Fabio Baldivia Pohl4, Zahra Moslehi5, Neil C. Henderson6,7, Catalina A. Vallejos7,8, Gioele La Manno5, Goncalo Castelo-Branco4,9, Anna Williams1*
1 Centre for Regenerative Medicine, Institute for Regeneration and Repair, Edinburgh Bioquarter, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU.
2 Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany. 3 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
4 Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
5 Laboratory of Neurodevelopmental Systems Biology, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
6 Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, UK.
7 MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
8 The Alan Turing Institute, 96 Euston Road, London, NW1 2DB, UK.
9 Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, 171 77 Stockholm, Sweden.
- anna.williams@ed.ac.uk, +44 (0) 131 651 9500
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.
This repository contains analysis code for the study above.