Géraud, C., Koch, P.-S., Zierow, J., Klapproth, K., Busch, K., Olsavszky, V., … Goerdt, S. (2017). GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis. Journal of Clinical Investigation, 127(3), 1099–1114. https://doi.org/10.1172/jci90086
GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis
|Author:||Géraud, Cyrill1; Koch, Philipp-Sebastian1; Zierow, Johanna1;|
1Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany
2Division of Cellular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
3Center for Medical Research
4Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
5Division of Molecular Genetics, DKFZ, Heidelberg, Germany
6Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland
7Division of Molecular Immunology, DKFZ, Heidelberg, Germany
8Division of Cellular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
9Division of Vascular Oncology and Metastasis (DKFZ-ZMBH Alliance), DKFZ, Heidelberg, Germany
10Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
|Online Access:||PDF Full Text (PDF, 9.4 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2019102434621
American Society for Clinical Investigation,
|Publish Date:|| 2019-10-24
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.
Journal of clinical investigation
|Pages:||1099 - 1114|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (DFG) SFB-TRR23, project B1 (to CG and SG); SFB-TRR77, project C3 (to SG); SFB 938, project H (to SG); GRK2099/RTG2099, project 7 (to CG and SG); and by grants from the Academy of Finland #284605 and #259872 (to SMK and TP).
|Academy of Finland Grant Number:||
284605 (Academy of Finland Funding decision)
259872 (Academy of Finland Funding decision)
© 2019 American Society for Clinical Investigation. The JCI is an open access journal.