Liver regeneration requires Yap1-TGFβ-dependent epithelial-mesenchymal transition in hepatocytes.
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Chronic failure of mechanisms that promote effective regeneration of dead hepatocytes causes replacement of functional hepatic parenchyma with fibrous scar and ultimately results 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 TGF-β since TGF-β signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis. Approach Wild type mice underwent partial hepatectomy (PH); TGF-β 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 TGF-β signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1flox/flox mice.TGF-β 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.Interactions between the TGF-β and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGF-β-enriched microenvironment and regenerate injured livers.The adult liver has an extraordinary ability to regenerate after injury despite the accumulation of scar-forming factors that normally block the proliferation and reduce the survival of residual liver cells. We discovered that liver cells manage to escape these growth-inhibitory influences by transiently becoming more like fibroblasts themselves, and showed that they do this by reactivating programs that are known to drive tissue growth during fetal development and in many cancers. Understanding how the liver is able to control programs that are involved in scarring and cancer may help develop new treatments for cirrhosis and liver cancer.
Published Version (Please cite this version)10.1016/j.jhep.2018.05.008
Publication InfoOh, Seh-Hoon; Swiderska-Syn, Marzena; Jewell, Mark L; Premont, Richard T; & Diehl, Anna Mae (2018). Liver regeneration requires Yap1-TGFβ-dependent epithelial-mesenchymal transition in hepatocytes. Journal of hepatology. 10.1016/j.jhep.2018.05.008. Retrieved from https://hdl.handle.net/10161/17085.
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Florence McAlister Distinguished Professor of Medicine
Our lab has a long standing interest in liver injury and repair. To learn more about the mechanisms that regulate this process, we study cultured cells, animal models of acute and chronic liver damage and samples from patients with various types of liver disease. Our group also conducts clinical trials in patients with chronic liver disease. We are particularly interested in fatty liver diseases, such as alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). <br
Assistant Professor in Medicine
Associate Professor in Medicine
Critical physiological events throughout the body are controlled by extracellular signals from neurotransmitters and hormones acting on cell surface receptors. Receptors transduce these signals to alter intracellular metabolism and cellular responsiveness through heterotrimeric G protein/second messenger pathways or through small GTP-binding protein/protein kinase cascades. The mechanisms that control the responsiveness of target organ G protein-coupled receptors include receptor ph
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