Brain matters: Unveiling the Distinct Contributions of Region, Age, and Sex to Glia diversity and CNS Function

Luise A. Seeker, Nadine Bestard-Cuche, Sarah Jäkel, 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

Abstract

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.

Datasets

1. white matter - all cells
Metadata
mapped_reference_assembly
mapped_reference_annotation
alignment_software
donor_id
self_reported_ethnicity_ontology_term_id
donor_cause_of_death
donor_living_at_sample_collection
organism_ontology_term_id
sample_uuid
sample_preservation_method
tissue_ontology_term_id
development_stage_ontology_term_id
sample_derivation_process
sample_source
suspension_derivation_process
suspension_dissociation_reagent
suspension_uuid
suspension_type
tissue_handling_interval
library_uuid
assay_ontology_term_id
library_starting_quantity
sequencing_platform
cell_type_ontology_term_id
author_cell_type
disease_ontology_term_id
sex_ontology_term_id
broad_cell_type
CauseOfDeath_category
10XBatch
SequencingPool
ID
AgeGroup
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
GRCh3845528 cells
Preview
Brain matters: Unveiling the Distinct Contributions of Region, Age, and Sex to Glia diversity and CNS Function

Analyze this study

Dataset 1
Download OmnibusX

Source data

https://cellxgene.cziscience.com/collections/9d63fcf1-5ca0-4006-8d8f-872f3327dbe9

Alias names

PMID37217978, PMC10204264

Cite this study

Seeker, L.A., Bestard-Cuche, N., Jäkel, S., Kazakou, N.L., Bøstrand, S.M., Wagstaff, L.J., Cholewa-Waclaw, J., Kilpatrick, A.M., Van Bruggen, D., Kabbe, M. and Baldivia Pohl, F., 2023. Brain matters: unveiling the distinct contributions of region, age, and sex to glia diversity and CNS function. Acta Neuropathologica Communications, 11(1), p.84. https://doi.org/10.1186/s40478-023-01568-z