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

Abstract

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 tissue-specific cell populations of oligodendrocyte precursor cells and astrocytes, and a spinal cord-enriched oligodendrocyte type that appears human-specific. 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, help explain pathological patterns of disease – essential knowledge for therapeutic strategies.

Regional and age‐related diversity of human mature oligodendrocytes

“…As noted, we did not observe such upregulation of immune‐related markers in microglia of SC versus such cells from other regions The observed difference between MOLs and microglia may be due to the specific interactions of OL lineage cells and neuronal subtypes in local microenvironments across different CNS regions as suggested by (Zonouzi et al, 2019). Seeker et al detected the expression of an immune‐gene expressing OL cluster in the human cervical spinal cord (Seeker et al, 2022).…”

Loss of the heterogeneous expression of flippase ATP11B leads to cerebral small vessel disease in a normotensive rat model

“…Heterogeneous expression of ATP11B in ECs does not relate to vessel type, as this occurs in the same vessel section, and all vessels studied are very small (by definition) and capillaries. We capitalised on our Human Cell Atlas single nuclei RNAsequencing data in adult human brain tissue [48] subsetting for ECs, categorising them of arteriole, capillary and venule origin using scSorter [21], and visualising ATP11B expression on an individual cell basis. Here, we found clear heterogeneity of ATP11B RNA expression in human brain small vessel ECs (Fig.…”

“…The density of gold particles per volume of EC profile (particles/µm 3 ) shows that one of the five ECs (EC5, red) has a far lower density of ATP11B-gold than the other four ECs (ECs 1-4; green, yellow, cyan, magenta) by a factor of between 9.5 and 14, compared to the level of background gold labelling seen in the nuclei (blue) of ECs 1 and 4 (green/magenta); 2.5 particles/µm 3 ). e Single nucleus heterogeneous expression of ATP11B transcript from snRNAseq in human adult CNS ECs, categorised into arteriole, capillary and venules [48]. f Heterogeneous expression of ATP11B (white) in human brain ECs of a vessel, yellow arrows indicate no ATP11B expression, green arrows indicate ATP11B expression.…”

Defining the pig microglial transcriptome reveals its core signature, regional heterogeneity, and similarity with human and rodent microglia

“…Examination of mouse single‐cell RNAseq data from the Dropviz dataset (Saunders et al, 2018 ) showed higher expression of complement genes and Cd74 in cerebellar microglia (Figure S5 ). A recent single nuclear RNAseq profiling of glial cells in the human CNS showed more expression of CD74 and HLA‐DRA in caudal regions compared to BA4 primary motor cortex (Seeker et al, in press ) indicating cross‐species conservation of regional microglial heterogeneity and across analytical platforms. We next validated spatial RNAseq profiles of pig microglia by performing in situ hybridization on the highly abundant C3 gene that was enriched in cerebellar microglia.…”