Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival
Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival
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DOI：
10.1038/s41586-018-0522-3
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发表时间：
2018-10-04
期刊：
影响因子：
64.8
通讯作者：
Lammert, Eckhard
中科院分区：
文献类型：
--
作者：
Lorenz, Linda;Axnick, Jennifer;Lammert, Eckhard
来自内皮细胞的血管分泌信号是细胞间通讯的重要组成部分，在器官生长、再生和疾病中起关键作用（1-4）。这些信号已经在多个器官中被鉴定和研究，包括肝脏、胰腺、肺、心脏、骨、骨髓、中枢神经系统、视网膜和一些癌症（1-4）。在这里，我们使用发育中的肝脏作为模型器官来研究血管分泌信号（5，6），并表明肝脏的生长速率在空间和时间上与该器官的血液灌注相关。通过操纵通过肝脏血管的血流，我们证明了血管灌注激活β 1整合素和血管内皮生长因子受体3（VEGFR 3）。值得注意的是，β 1整联蛋白和VEGFR 3都是肝细胞生长因子正常产生、肝细胞存活和肝脏生长严格需要的。成年小鼠肝脏的离体灌注和人肝内皮细胞的体外机械拉伸说明单独的机械转导足以打开血管分泌信号。当内皮细胞被机械拉伸时，血管分泌信号触发原代人肝细胞的体外增殖和存活。我们的研究结果揭示了血管内皮细胞中的信号通路，该通路将血液灌注和机械转导转化为器官生长和维持。
Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease(1-4). These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers(1-4). Here we use the developing liver as a model organ to study angiocrine signals(5,6), and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates beta 1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both beta 1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance.