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Liver regeneration requires Yap1-TGF?-dependent epithelial-mesenchymal transition in hepatocytes.

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 TGF?, since TGF? signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis. METHODS:Wild-type mice underwent 70% partial hepatectomy (PH); TGF? expression and signaling were evaluated in intact tissue and primary hepatocytes before, during, and after the period of maximal hepatocyte proliferation that occurs from 24-72?h after PH. To determine the role of Yap1 in regulating TGF? signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1flox/flox mice. RESULTS:TGF? 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 1?1. Deleting Yap1 from hepatocytes blocked their nuclear accumulation of pSmad2 and EMT-like response, as well as their proliferation. CONCLUSION:Interactions between the TGF? and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGF?-enriched microenvironment and regenerate injured livers. LAY SUMMARY: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. They do this by reactivating programs that are known to drive tissue growth during fetal development and in many cancers. Understanding how the liver can control programs that are involved in scarring and cancer may help in the development of new treatments for cirrhosis and liver cancer.

SUBMITTER: Oh SH

PROVIDER: S-EPMC6349217 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Liver regeneration requires Yap1-TGFβ-dependent epithelial-mesenchymal transition in hepatocytes.

Oh Seh-Hoon SH Swiderska-Syn Marzena M Jewell Mark L ML Premont Richard T RT Diehl Anna Mae AM

Journal of hepatology 20180523 2

<h4>Background & aims</h4>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 mat ...[more]

PMID: 29758331

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Project description:Healthy livers have a remarkable regenerative capacity for reconstructing functional hepatic parenchyma after 70% partial hepatectomy (PH). Hepatocytes, usually quiescent in normal healthy livers, proliferate to compensate for hepatic loss after PH. However, the mechanism of hepatocyte involvement in liver regeneration remains unclear. Hedgehog (Hh) pathway plays an important role in tissue reconstitution by regulating epithelial-to-mesenchymal transition (EMT) in liver disease. MicroRNA (miRNA) is involved in cell proliferation and differentiation during embryonic development and carcinogenesis. It was recently reported that miR-378 inhibits transdifferentiation of hepatic stellate cells into myofibroblasts by suppressing Gli-Krüppel family member 3 (Gli3), the Hh-target gene. We hypothesized that miR-378 influences EMT in hepatocytes by interfering with Hh signaling during liver regeneration. As hepatocytes were highly proliferative after PH in mice, miR-378 and epithelial marker, Ppar-g or E-cadherin were downregulated, whereas both Hh activators, Smoothened (Smo) and Gli3, and the EMT-inducing genes, Tgfb, Snail and Vimentin, were upregulated in the regenerating livers and in hepatocytes isolated from them. Compared to cells with or without scramble miRNA, primary hepatocytes transfected with miR-378 inhibitor contained higher levels of Gli3 with increased expression of the EMT-promoting genes, Tgfb, Snail, Col1a1, and Vimentin, suggesting that miR-378 influenced EMT in hepatocytes. Smo-depleted hepatocytes isolated from PH livers of Smo-flox mice showed downregulation of EMT-promoting genes and Gli3, with upregulation of miR-378 and E-cadherin compared to Smo-expressing hepatocytes from PH liver. In addition, delivery hepatocyte-specific AAV8 viral vector bearing Cre recombinase into Smo-flox mice impeded EMT in Smo-suppressed hepatocytes of PH liver, indicating that Smo is critical for regulating hepatocyte EMT. Furthermore, the application of miR-378 mimic into mice with PH delayed liver regeneration by interrupting hepatocyte EMT. In conclusion, our results demonstrate that miR-378 is involved in hepatocyte EMT by regulating Hh signaling during liver regeneration.

Dataset Information

Liver regeneration requires Yap1-TGF?-dependent epithelial-mesenchymal transition in hepatocytes.

Publications

Liver regeneration requires Yap1-TGFβ-dependent epithelial-mesenchymal transition in hepatocytes.

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