Abstract
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. 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 24-72 h 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. 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. 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. 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.
Highlights
Adult liver has robust regenerative capacity as demonstrated by efficient restitution of fully functional liver mass within days to weeks after acute 70% partial hepatectomy (PH) in mice and humans, respectively.[1]
Our study indicates that populations of hepatocytes undergo a process that resembles epithelial-to-mesenchymal transition (EMT) during the time period when hepatocytes proliferate so that the liver can regenerate effectively after partial hepatectomy
This insight is intriguing because partial hepatectomy has long been used to enhance drug-induced hepatocarcinogenesis in rodents,[35] and chronic hepatic regenerative activity increases the risk of cancer development in many liver diseases.[36,37,38]
Summary
Adult liver has robust regenerative capacity as demonstrated by efficient restitution of fully functional liver mass within days to weeks after acute 70% partial hepatectomy (PH) in mice and humans, respectively.[1] Paradoxically, chronically dysregulated repair of even minor liver damage causes defective recovery of healthy liver parenchyma and results in cirrhosis and/or liver cancer Preventing these bad outcomes of liver injury is necessary to reduce mortality from liver disease, a major cause of premature death in adulthood worldwide.[2] Success has been elusive because of relatively limited understanding of the mechanisms that promote effective reconstruction of this complex organ in adults. 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
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