CD146 coordinates brain endothelial cell-pericyte communication for blood-brain barrier development
CD146 coordinates brain endothelial cell-pericyte communication for blood-brain barrier development
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CD146 协调脑内皮细胞-周细胞通讯以促进血脑屏障的发育
DOI：
10.1073/pnas.1710848114
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发表时间：
2017-09-05
影响因子：
11.1
通讯作者：
Yan, Xiyun
中科院分区：
文献类型：
--
作者：
Chen, Jianan;Luo, Yongting;Yan, Xiyun
血脑屏障（BBB）在中枢神经系统和外周血液循环之间建立起保护性界面，对CNS的稳态至关重要。当内皮细胞（EC）侵入CNS时，BBB形成开始，并且周细胞在胚胎发生期间被募集到新生血管。尽管在血脑屏障的发展过程中，周细胞-EC相互作用的基本功能，协调周细胞-EC的行为和通信的分子机制仍然不完全清楚。在这里，我们报告了一个单细胞受体，CD 146，在BBB诱导和成熟的阶段，在血管系统中呈现动态表达模式，协调EC和周细胞的相互作用，并协调BBB的发展时空。在小鼠脑中，CD 146首先在没有周细胞覆盖的未成熟毛细血管的脑血管内皮细胞中表达;随着周细胞覆盖的增加，CD 146只能在周细胞中检测到，而不能在脑血管内皮细胞中检测到。特异性缺失小鼠EC中的Cd 146导致脑内皮细胞claudin-5表达减少和BBB破坏。通过分析小鼠与特定缺失的Cd 146在周细胞，这有缺陷的周细胞覆盖和血脑屏障的完整性，我们表明，CD 146作为一个辅助受体的PDGF受体β介导周细胞招聘脑血管内皮细胞。此外，我们还发现贴壁的周细胞通过分泌TGF-β 1下调内皮细胞CD 146，促进血脑屏障的进一步成熟。这些结果表明，CD 146的动态表达控制EC和周细胞的行为，从而协调成熟和稳定的BBB的形成。
The blood-brain barrier (BBB) establishes a protective interface between the central neuronal system and peripheral blood circulation and is crucial for homeostasis of the CNS. BBB formation starts when the endothelial cells (ECs) invade the CNS and pericytes are recruited to the nascent vessels during embryogenesis. Despite the essential function of pericyte-EC interaction during BBB development, the molecular mechanisms coordinating the pericyte-EC behavior and communication remain incompletely understood. Here, we report a single cell receptor, CD146, that presents dynamic expression patterns in the cerebrovasculature at the stages of BBB induction and maturation, coordinates the interplay of ECs and pericytes, and orchestrates BBB development spatiotemporally. In mouse brain, CD146 is first expressed in the cerebrovascular ECs of immature capillaries without pericyte coverage; with increased coverage of pericytes, CD146 could only be detected in pericytes, but not in cerebrovascular ECs. Specific deletion of Cd146 in mice ECs resulted in reduced brain endothelial claudin-5 expression and BBB breakdown. By analyzing mice with specific deletion of Cd146 in pericytes, which have defects in pericyte coverage and BBB integrity, we demonstrate that CD146 functions as a coreceptor of PDGF receptor-beta to mediate pericyte recruitment to cerebrovascular ECs. Moreover, we found that the attached pericytes in turn down-regulate endothelial CD146 by secreting TGF-beta 1 to promote further BBB maturation. These results reveal that the dynamic expression of CD146 controls the behavior of ECs and pericytes, thereby coordinating the formation of a mature and stable BBB.