A molecular atlas of cell types and zonation in the brain vasculature

Abstract

Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.

Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain

“…Mural cells have two subtypes: pericytes, which associate with capillaries, and smooth muscle alpha actin (SMA) cells, which associate with larger-bore vasculature and control blood flow (Hill et al, 2015; Hughes and Chan-Ling, 2004; Nehls and Drenckhahn, 1991). A single IC (IC 13) appeared to encode this distinction, with pericyte marker Vtn as the strongest loading gene (Figure 2C)(Vanlandewijck et al, 2018). Other enriched genes suggest specialized pericyte function.…”

“…For example, expression of a potassium channel activated by diphosphate levels (encoded by Kcnj8 and Abcc9 ) and an ADP-ribosyltransferase ( Art3 ) suggest signaling machinery that couples dinucleotide metabolites to membrane potential and post-translational modification. Among SMA cells, Acta2 expression correlates with a veinous versus arterial distribution (Vanlandewijck et al, 2018). IC 19 represented this difference in a graded rather than categorical way, as Rgs5 / Acta2 expression and IC cell scores were continuously, rather than bimodally, distributed across these cells (Figure 2C)(Vanlandewijck et al, 2018).…”

“…Among SMA cells, Acta2 expression correlates with a veinous versus arterial distribution (Vanlandewijck et al, 2018). IC 19 represented this difference in a graded rather than categorical way, as Rgs5 / Acta2 expression and IC cell scores were continuously, rather than bimodally, distributed across these cells (Figure 2C)(Vanlandewijck et al, 2018). Our data also identify new mural cell diversity.…”

“…While endothelial cells are known as the constituent cell class of blood vessels, fibroblast-like cells are a recently-described population with unknown function that inhabit the perivascular space in the brain (Vanlandewijck et al, 2018). We found 7 subclusters each of endothelial (n=16,248) and fibroblast-like (n=1,587) cells (Figure 2D,E).…”

“…We identified endothelial ICs (Figure 2E) with strong contributions from genes with arterial (IC 5 and 20) and veinous (IC 3 and 12) expression, suggesting heterogeneity related to vessel type (Data S4G) (Vanlandewijck et al, 2018). These genes (e.g.…”