周细胞
壁细胞
血脑屏障
细胞生物学
表型
生物
转录组
细胞
内皮干细胞
电池类型
基因表达
神经科学
基因
中枢神经系统
遗传学
体外
作者
Maarja Andaloussi Mäe,Liqun He,Sofia Nordling,Elisa Vázquez-Liébanas,Khayrun Nahar,Bongnam Jung,Xidan Li,Bryan C. Tan,Juat Chin Foo,Amaury Cazenave-Gassiot,Markus R. Wenk,Yvette Zarb,Bàrbara Laviña,Susan E. Quaggin,Marie Jeansson,Chengua Gu,David L. Silver,Michael Vanlandewijck,Eugene C. Butcher,Annika Keller,Christer Betsholtz
标识
DOI:10.1161/circresaha.120.317473
摘要
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.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.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 BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB.By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.
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