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

dc.contributor.author Oh, Seh-Hoon
dc.contributor.author Swiderska-Syn, Marzena
dc.contributor.author Jewell, Mark L
dc.contributor.author Premont, Richard T
dc.contributor.author Diehl, Anna Mae
dc.date.accessioned 2018-06-01T13:41:04Z
dc.date.available 2018-06-01T13:41:04Z
dc.date.issued 2018-05-11
dc.identifier S0168-8278(18)32054-3
dc.identifier.issn 0168-8278
dc.identifier.issn 1600-0641
dc.identifier.uri https://hdl.handle.net/10161/17085
dc.description.abstract 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.
dc.language eng
dc.publisher Elsevier BV
dc.relation.ispartof Journal of hepatology
dc.relation.isversionof 10.1016/j.jhep.2018.05.008
dc.subject Hepatocyte reprogramming
dc.subject Liver regeneration
dc.title Liver regeneration requires Yap1-TGFβ-dependent epithelial-mesenchymal transition in hepatocytes.
dc.type Journal article
duke.contributor.id Oh, Seh-Hoon|0721827
duke.contributor.id Premont, Richard T|0095901
duke.contributor.id Diehl, Anna Mae|0314922
dc.date.updated 2018-06-01T13:41:02Z
pubs.organisational-group School of Medicine
pubs.organisational-group Duke
pubs.organisational-group Duke Institute for Brain Sciences
pubs.organisational-group University Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Medicine, Gastroenterology
pubs.organisational-group Medicine
pubs.organisational-group Clinical Science Departments
pubs.publication-status Published
duke.contributor.orcid Premont, Richard T|0000-0002-8053-5026


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