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

• 成果类型: Article
• 署名作者: Walchli, Thomas; Ghobrial, Moheb; Schwab, Marc; Takada, Shigeki; Zhong, Hang; Suntharalingham, Samuel; Vetiska, Sandra; Gonzalez, Dayme Rodrigues; Wu, Ruilin; Rehrauer, Hubert; Dinesh, Anuroopa; Yu, Kai; Chen, Edward L. Y.; Bisschop, Jeroen; Farnhammer, Fiona; Mansur, Ann; Kalucka, Joanna; Tirosh, Itay; Regli, Luca; Schaller, Karl; Frei, Karl; Ketela, Troy; Bernstein, Mark; Kongkham, Paul; Carmeliet, Peter; Valiante, Taufik; Dirks, Peter B.; Suva, Mario L.; Zadeh, Gelareh; Tabar, Viviane; Schlapbach, Ralph; Jackson, Hartland W.; De Bock, Katrien; Fish, Jason E.; Monnier, Philippe P.; Bader, Gary D.; Radovanovic, Ivan
• 署名单位: University of Toronto; University Health Network Toronto; Krembil Research Institute; University of Toronto; University of Zurich; University of Zurich; University Zurich Hospital; University of Zurich; University Zurich Hospital; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Zurich; Kyoto University; University of Toronto; University Health Network Toronto; Krembil Research Institute; University of Toronto; University of Zurich; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Toronto; University of Toronto; University Health Network Toronto; University of Toronto; Sinai Health System Toronto; Lunenfeld Tanenbaum Research Institute; University of Toronto; Aarhus University; Weizmann Institute of Science; University of Geneva; University of Geneva; University of Toronto; University of Toronto; University of Toronto; University Health Network Toronto; Flanders Institute for Biotechnology (VIB); KU Leuven; KU Leuven; Sun Yat Sen University; Aarhus University; University of Toronto; University Health Network Toronto; Krembil Research Institute; University of Toronto; University of Toronto; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Hospital for Sick Children (SickKids); Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; Memorial Sloan Kettering Cancer Center; University of Toronto; Ontario Institute for Cancer Research; University of Toronto; Peter Munk Cardiac Centre; University Health Network Toronto; Krembil Research Institute; University of Toronto; University of Toronto
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4816
• DOI: 10.1038/s41586-024-07493-y
• 发表日期: 2024-08-15
• 页码: 603-+
• 关键词: spatial reconstruction; molecular-mechanisms; barrier permeability; cns angiogenesis; key role; nogo-a; protein; HEALTH; gpr124; integrity

摘要

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(1). 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.