Marked regional glial heterogeneity in the human white matter of the central nervous system

Luise A. Seeker, Nadine Bestard-Cuche, Sarah Jaekel, Nina-Lydia Kazakou, Sunniva M. K. Bøstrand, Laura J. Wagstaff, Justyna Cholewa-Waclaw, Alastair M. Kilpatrick, David Van Bruggen, Mukund Kabbe, Fabio Baldivia Pohl, Zahra Moslehi, Neil C. Henderson, Catalina A. Vallejos, Gioele La Manno, Goncalo Castelo-Branco, Anna Williams

The myelinated white matter tracts of the central nervous system (CNS) are essential for fast transmission of electrical impulses and are commonly affected in neurodegenerative diseases. However, these often uniquely human diseases differentially affect white matter regions, at various ages and between males and females, and we hypothesised that this is secondary to physiological variation in white matter glia with region, age and sex. Using single nucleus RNA sequencing of healthy human post-mortem samples, we find marked glial heterogeneity with tissue region (primary motor cortex, cerebellum, cervical spinal cord), with region-specific cell populations of oligodendrocyte precursor cells and astrocytes, and a spinal cord-enriched oligodendrocyte type that appears human-selective. Spinal cord microglia but not astrocytes show a more activated phenotype compared to brain. These regional effects, with additional differentially expressed genes with age and sex in all glial lineages, may help explain pathological patterns of disease – essential knowledge for therapeutic strategies.

This repository contains analysis code for the study above.