Single-cell atlas of the human brain vasculature across development, adulthood and disease (Extra Individuals)
A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood. Here, we performed single-cell RNA sequencing of 606,380 freshly isolated endothelial, perivascular and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We uncover extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across eight vascular-dependent Central Nervous System (CNS) pathologies including brain tumors and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict numerous endothelial-to-perivascular cell ligand-receptor crosstalk including immune-related and angiogenic pathways, thereby unraveling a central role for the endothelium within brain neurovascular unit signaling networks. Our single-cell brain atlas provides insight 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 Overall design: We constructed a human brain vasculature single-cell atlas using samples from fetal as well as adult control (undiseased atlas) and diseased brains, including adult brain vascular malformations and brain tumors (diseased atlas). We acquired freshly isolated cells (both FACS-sorted ECs and unsorted ECs and PVCs from 8 individual fetuses and from 61 adult brain specimens (from 61 individual patients), covering adult temporal lobe (TL) controls and adult vascular-dependent pathologies, namely, brain arteriovenous malformation (AVM), lower-grade glioma (LGG), glioblastoma (GBM), lung cancer brain metastasis (MET) and meningioma (MEN)