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 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 Article has an altmetric score of 10

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 6

Liver endothelial GATA4 is required for maintenance of discontinuous LSEC differentiation.

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Liver endothelial GATA4 is required for maintenance of discontinuous LSE...
(A) Expression of LYVE1, STAB2, and CD31 in the liver of Stab2-Cre Gata4fl/fl embryos at E11.5. IHC (upper panels) and quantification (lower panels) based on IF images of LYVE1, STAB2, and CD31 (n = 4). Scale bars: 100 μm. Western blot of LYVE1 and GAPDH with quantification of densitometric data (n = 5) (right). (B) Transmission electron microscopy (TEM) of the liver of Stab2-Cre Gata4fl/fl embryos at E11.5. Arrows indicate formation of a basement membrane (n = 4). (C) Co-IF of STAB2 and CD31 in the liver of Stab2-Cre Gata4fl/fl (n = 4) (left) and Lyve1-Cre Gata4fl/fl (n = 3) (right) embryos at E11.5. Scale bars: 20 μm (left) and 10 μm (right). (D) IF of CD31 in the fetal liver of Stab2-Cre Gata4fl/fl embryos at E10.5 shows increased expression of CD31 in the endothelium of mutant embryos as an indicator of early hepatic capillarization. Scale bars: 20 μm (upper panels) and 10 μm (lower panels) (n = 2). Student’s t test; ***P < 0.001.