GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis
Cyrill Géraud, … , Kai Schledzewski, Sergij Goerdt
Cyrill Géraud, … , Kai Schledzewski, Sergij Goerdt
Published March 1, 2017; First published February 20, 2017
Citation Information: J Clin Invest. 2017;127(3):1099-1114. https://doi.org/10.1172/JCI90086.
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Research Article Hepatology Vascular biology

GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis

Abstract

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.

Authors

Cyrill Géraud, Philipp-Sebastian Koch, Johanna Zierow, Kay Klapproth, Katrin Busch, Victor Olsavszky, Thomas Leibing, Alexandra Demory, Friederike Ulbrich, Miriam Diett, Sandhya Singh, Carsten Sticht, Katja Breitkopf-Heinlein, Karsten Richter, Sanna-Maria Karppinen, Taina Pihlajaniemi, Bernd Arnold, Hans-Reimer Rodewald, Hellmut G. Augustin, Kai Schledzewski, Sergij Goerdt

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Figure 1

LSECs represent the only intersection of GATA4 and STAB2 expression during development of the embryo.

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LSECs represent the only intersection of GATA4 and STAB2 expression duri...
(A) Murine liver (mLiver) and human liver (hLiver) show GATA4 in CD32b+ LSECs on co-immunofluorescence (co-IF). Expression of GATA4 detected by Western blot in rat LSECs (rLSEC) and mouse LSECs (mLSEC), but not in rLMECs and bEnd5 murine brain ECs (n = 3). Scale bars: 20 μm and 10 μm (inset). (B) IHC of STAB2 and CD31 at E13.5 (n = 5). (C) Co-IF of GATA4 with STAB2 or CD31 in fetal liver and heart of WT embryos at E10.5 (n = 2). Scale bars: 10 μm.