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Brain Vasculature Cell Features Spelled Out in Single-Cell Sequencing Atlas

NEW YORK – Researchers at the University of Toronto, the University of Zurich, and other international centers have assembled a single-cell atlas representing cell types involved in human brain vasculature across life stages and in relation to conditions such as brain tumors or vascular malformation — work they outlined in Nature on Wednesday.

"A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide," co-first and corresponding author Thomas Wälchli, an experimental and translational neuroscience and neurosurgery researcher affiliated with the University of Toronto, the University of Zurich, and the University Hospital Zurich, and colleagues wrote, noting that the "cellular and molecular architecture of the human brain vasculature remains incompletely understood."

Using fluorescence-activated cell sorting, 10x Genomics Chromium single-cell RNA sequencing, and computational analyses, the researchers profiled expression patterns in 606,380 freshly isolated cells from 117 samples. The samples represented human fetuses, adult control individuals, and adult individuals affected by central nervous system disease with ties to the vascular system, including brain arteriovenous (AV) malformation, meningioma, glioma, glioblastoma, and metastatic lung cancer brain tumors.

"Our human vascular brain atlas provides a basis for understanding the organizing principles and single-cell heterogeneity of universal, specialized, and activated endothelial and [perivascular cells] with broad implications for physiology and medicine," the authors wrote, "and serves as a powerful publicly available reference for the field."

The single-cell gene expression profiles revealed 18 main brain cell types across endothelial, perivascular, and other cell types, the team reported, providing a look at cellular heterogeneity and diversity in the human brain vasculature system. The single-cell profiles — validated with corresponding bulk RNA-seq data — also made it possible to distinguish the vascular cell types and expression markers found in different life stages and disease scenarios.

Based on expression profiles in 243,521 brain vascular endothelial cells originating in 43 fetal, adult/control, or 29 brain pathology samples, for example, the researchers saw clusters of cells from arteries, arterioles, veins, venules, capillaries, and angiogenic capillary; proliferating cells; and other cell types originating in distinct AV locations.

"Brain vascular [endothelial cells] are organized along the human brain AV axis, referred to as zonation," the authors explained, noting that they identified 14 main endothelial cell clusters and 44 endothelial cell subclusters based on the differentially expressed genes found in the individual cells profiled.

More broadly, the study's authors suggested that the single-cell sequence collection can serve as a resource for informing future studies of the human brain and on vascular system-related conditions affecting the brain.

"Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control, and diseased human brain vasculature and serves as a powerful reference for future studies," they wrote.

In samples collected from individuals with brain disease, meanwhile, the team unearthed gene expression shifts consistent with the reactivation of programs present in fetal samples, along with changes in cell differentiation, cellular interactions, MHC class II-related immune activity, and the activity of genes linked to CNS specificity — results backed up by transcriptomic features previously found with bulk RNA-seq data on mouse blood-brain-barrier samples.

"Together, these data indicate that signaling axes driving vascular growth during fetal brain development are silenced in the adult control brain and reactivated in the vasculature of brain tumors and brain vascular malformations," the authors reported, "and that common dysregulated pathways are observed in the pathological brain vascular endothelium across diseases."