In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the clearance of activated hepatic stellate cells, either by apoptosis or by reversion towards a quiescentlike state, a process denominated deactivation. Thus, deactivation of active hepatic stellate cells has emerged as a novel and promising therapeutic approach for liver fibrosis. However, our knowledge of the master regulators involved in the de/activation of fibrotic hepatic stellate cells is still limited. The transcription factor GATA4 has been previously shown to play an important role in embryonic hepatic stellate cells quiescence. In this work, we show that lack of GATA4 in adult mice causes hepatic stellate cell activation and consequently, liver fibrosis. During regression of liver fibrosis, Gata4 is reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promotes liver fibrosis regression in CCl4-treated mice. GATA4 induces changes in the expression of fibrogenic and antifibrogenic genes promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly represses EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.

Pancreatic heterotopia is defined as pancreatic tissue outside its normal location in the body and anatomically separated from the pancreas. In this work we have analyzed the stomach glandular epithelium of Gata4 flox/flox; Pdx1‐Cre mice (Gata4KO mice). We found that Gata4KO glandular epithelium displays an atypical morphology similar to the cornified squamous epithelium and exhibits upregulation of forestomach markers. The developing gastric units fail to form properly, and the glandular epithelial cells do not express markers of gastric gland in the absence of GATA4. Of interest, the developing glands of the Gata4KO stomach express pancreatic cell markers. Furthermore, a mass of pancreatic tissue located in the subserosa of the Gata4KO stomach is observed at adult stages. Heterotopic pancreas found in Gata4‐deficient mice contains all three pancreatic cell lineages: ductal, acinar, and endocrine. Moreover, Gata4 expression is downregulated in ectopic pancreatic tissue of some human biopsy samples. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.