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J. Hepatol., Volume 69, Issue 2, August 2018, Pages 359-367 | https://doi.org/10.1016/j.jhep.2018.05.008
Liver regeneration requires Yap1-TGFβ-dependent epithelial-mesenchymal transition in hepatocytes
Seh-Hoon Oh, Marzena Swiderska-Syn, Mark L. Jewell, Richard T. Premont, Anna Mae Diehl*
Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
*Corresponding author.
Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
*Corresponding author.
Abstract
Background & Aims
Chronic failure of mechanisms that promote effective regeneration of dead hepatocytes causes replacement of functional hepatic parenchyma with fibrous scar tissue, ultimately resulting in cirrhosis. Therefore, defining and optimizing mechanisms that orchestrate effective regeneration might prevent cirrhosis. We hypothesized that effective regeneration of injured livers requires hepatocytes to evade the growth-inhibitory actions of TGFβ, since TGFβ signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis.
Methods
Wild-type mice underwent 70% partial hepatectomy (PH); TGFβ expression and signaling were evaluated in intact tissue and primary hepatocytes before, during, and after the period of maximal hepatocyte proliferation that occurs from 24-72h after PH. To determine the role of Yap1 in regulating TGFβ signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1flox/flox mice.
Results
TGFβ expression and hepatocyte nuclear accumulation of pSmad2 and Yap1 increased in parallel with hepatocyte proliferative activity after PH. Proliferative hepatocytes also upregulated Snai1, a pSmad2 target gene that promotes epithelial-to-mesenchymal transition (EMT), suppressed epithelial genes, induced myofibroblast markers, and produced collagen 1α1. Deleting Yap1 from hepatocytes blocked their nuclear accumulation of pSmad2 and EMT-like response, as well as their proliferation.
Conclusion
Interactions between the TGFβ and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGFβ-enriched microenvironment and regenerate injured livers.
Keywords: Liver regeneration; Hepatocyte reprogramming; Epithelial-mesenchymaltransition
논문정보
- Research article
- 2018년 08월 (BRIC 등록일 2018-07-25)
- 국외 연구진
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