Single-cell atlas of the human brain vasculature across development, adulthood and disease

Thomas Wälchli (), Moheb Ghobrial, Marc Schwab, Shigeki Takada, Hang Zhong, Samuel Suntharalingham, Sandra Vetiska, Daymé Rodrigues Gonzalez, Ruilin Wu, Hubert Rehrauer, Anuroopa Dinesh, Kai Yu, Edward L. Y. Chen, Jeroen Bisschop, Fiona Farnhammer, Ann Mansur, Joanna Kalucka, Itay Tirosh, Luca Regli, Karl Schaller, Karl Frei, Troy Ketela, Mark Bernstein, Paul Kongkham, Peter Carmeliet, Taufik Valiante, Peter B. Dirks, Mario L. Suva, Gelareh Zadeh, Viviane Tabar, Ralph Schlapbach, Hartland W. Jackson, Katrien Bock, Jason E. Fish, Philippe P. Monnier, Gary D. Bader and Ivan Radovanovic
Additional contact information
Thomas Wälchli: University of Toronto
Moheb Ghobrial: University of Toronto
Marc Schwab: University of Toronto
Shigeki Takada: University of Toronto
Hang Zhong: University of Toronto
Samuel Suntharalingham: University of Toronto
Sandra Vetiska: University of Toronto
Daymé Rodrigues Gonzalez: ETH Zurich/University of Zurich
Ruilin Wu: University of Toronto
Hubert Rehrauer: ETH Zurich/University of Zurich
Anuroopa Dinesh: Mount Sinai Health System
Kai Yu: University of Toronto
Edward L. Y. Chen: Mount Sinai Health System
Jeroen Bisschop: University of Toronto
Fiona Farnhammer: University of Toronto
Ann Mansur: University of Toronto
Joanna Kalucka: Aarhus University
Itay Tirosh: Weizmann Institute of Science
Luca Regli: University Hospital Zurich
Karl Schaller: University of Geneva
Karl Frei: University of Zurich and University Hospital Zurich
Troy Ketela: University of Toronto
Mark Bernstein: University of Toronto
Paul Kongkham: University of Toronto
Peter Carmeliet: VIB & Department of Oncology, KU Leuven
Taufik Valiante: University of Toronto
Peter B. Dirks: University of Toronto
Mario L. Suva: Massachusetts General Hospital and Harvard Medical School
Gelareh Zadeh: University of Toronto
Viviane Tabar: Memorial Sloan Kettering Cancer Center
Ralph Schlapbach: ETH Zurich/University of Zurich
Hartland W. Jackson: Mount Sinai Health System
Katrien Bock: Department of Health Sciences and Technology; Swiss Federal Institute of Technology (ETH Zurich)
Jason E. Fish: University of Toronto
Philippe P. Monnier: University of Toronto
Gary D. Bader: Mount Sinai Health System
Ivan Radovanovic: University of Toronto

Nature, 2024, vol. 632, issue 8025, 603-613

Abstract: Abstract 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 understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells 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 identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours 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 substantial endothelial-to-perivascular cell ligand–receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07493-y

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