GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis
GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis
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DOI：
10.1172/jci90086
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发表时间：
2017-03-01
影响因子：
15.9
通讯作者：
Goerdt, Sergij
中科院分区：
文献类型：
--
作者：
Geraud, Cyrill;Koch, Philipp-Sebastian;Goerdt, Sergij
微血管内皮细胞（EC）越来越多地被认为是其微环境的器官特异性看门人。微血管内皮细胞通过血管分泌因子（包括分泌的生长因子（血管因子）、细胞外基质分子和跨膜蛋白）在其器官特异性血管龛中指导邻近细胞。然而，驱动器官特异性微血管转录程序，从而调节血管多样性的分子调控因子在很大程度上是难以捉摸的。与形成连续细胞层的其他EC相比，肝窦状内皮细胞（LSEC）构成不连续的可渗透微血管。在这里，我们已经表明，转录因子GATA 4控制鼠LSEC规范和功能。Gata 4的LSEC限制性缺失导致不连续的肝血窦转化为连续的毛细血管。毛细血管化的特点是异位基底膜沉积，形成一个连续的EC层，并增加表达VE-钙粘蛋白。相应地，异位表达的GATA 4在培养的连续EC介导的下调连续EC相关的转录和上调LSEC相关基因。在胚胎发生过程中，从不连续的LSEC到连续的EC的转变导致肝脏发育不全、纤维化和造血祖细胞定植受损，从而导致贫血和胚胎死亡。因此，GATA 4作为肝脏微血管特化和器官特异性血管能力获得的主要调节因子，这对于肝脏发育是不可或缺的。这些数据也确立了肝脏微血管在胚胎造血中的重要作用。
Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular ECs instruct neighboring cells in their organ-specific vascular niches through angiocrine factors, which include secreted growth factors (angiokines), extracellular matrix molecules, and transmembrane proteins. However, the molecular regulators that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity are largely elusive. In contrast to other ECs, which form a continuous cell layer, liver sinusoidal ECs (LSECs) constitute discontinuous, permeable microvessels. Here, we have shown that the transcription factor GATA4 controls murine LSEC specification and function. LSEC-restricted deletion of Gata4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition, formation of a continuous EC layer, and increased expression of VE-cadherin. Correspondingly, ectopic expression of GATA4 in cultured continuous ECs mediated the downregulation of continuous EC-associated transcripts and upregulation of LSEC-associated genes. The switch from discontinuous LSECs to continuous ECs during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells, resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence, which are indispensable for liver development. The data also establish an essential role of the hepatic microvasculature in embryonic hematopoiesis.