Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss

作者：M. Mäe, Liqun He, S. Nordling, E. Vázquez-Liébanas, Khayrun Nahar, Bongnam Jung, Xi-Dan Li, Bryan C. Tan, Juat Chin Foo, A. Cazenave-Gassiot, M. Wenk, Yvette Zarb, B. Lavina, S. Quaggin, M. Jeansson, Chengua Gu, D. Silver, M. Vanlandewijck, E. Butcher, Annika Keller, C. Betsholtz · 发表于：Circulation Research · 年份：2020 · DOI：10.1161/circresaha.120.317473 · 被引用次数：175 · 研究领域：Medicine

Rationale: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive. Objective: To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level, and to correlate them with regional heterogeneities in BBB function and vascular phenotype. Methods and Results: We reveal transcriptional, morphological and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses and immunofluorescent detection of protein expression in pericyte-deficient adult Pdgfbret/ret mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult Pdgfbret/ret brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BB...