Hepatic progenitor cell activation in liver repair

Bria, Adam; Jorgensen, Marda; Zhou, Junmei; Sun, Xiaowei; Cao, Qi; Petersen, Bryon E.; Pi, Liya

doi:10.1016/j.livres.2017.08.002

Cited by 37 publications

(37 citation statements)

References 75 publications

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“…Previous studies have demonstrated that ductular reaction cells appear during chronic liver injury and differentiated into hepatocytes, thus maintaining hepatic homeostasis (Fellous et al 2009 ; Passman et al 2015 ; Bria et al 2017 ). In our study, we first confirmed that severe liver injury existed in human chronic liver injury (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The self-renewal capacity of mature hepatocytes contributes to adult liver homeostasis and regeneration; however, the nature of impaired regeneration resulting from chronic liver damage remains unclear (Forbes and Newsome 2016 ; Chien et al 2018 ; López-Luque and Fabregat 2018 ), and the capacity for self-renewal is overwhelmed following persistent chronic liver injury. In this condition, ductular reaction cells (known as HPCs) expressing SOX9 and cell keratin 19 (CK19) emerge, become activated and then differentiate into functional hepatocytes (Fellous et al 2009 ; Passman et al 2015 ; Bria et al 2017 ). However, the relative contribution of HPCs to parenchymal regeneration remains controversial (Michalopoulos and Khan 2015 ; Reid 2015 ; Kopp et al 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Autophagy promotes hepatic differentiation of hepatic progenitor cells by regulating the Wnt/β-catenin signaling pathway

Chen

et al. 2019

J Mol Hist

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Hepatic progenitor cells (HPCs) can be activated when the liver suffers persistent and severe damage and can differentiate into hepatocytes to maintain liver regeneration and homeostasis. However, the molecular mechanism underlying the hepatic differentiation of HPCs is unclear. Therefore, in this study, we aimed to investigate the roles of autophagy and the Wnt/β-catenin signaling pathway during hepatic differentiation of HPCs in vivo and in vitro. First, immunohistochemistry, immunofluorescence and electron microscopy showed that Atg5 and β-catenin were highly expressed in human fibrotic liver and mouse liver injury induced by feeding a 50% choline-deficient diet plus 0.15% ethionine solution in drinking water (CDE diet) for 21 days; in addition, these factors were expressed in CK19-positive HPCs. Second, Western blotting and immunofluorescence confirmed that CK19-positive HPCs incubated in differentiation medium for 7 days can differentiate into hepatocytes and that differentiated HPCs were able to take up ICG and secrete albumin and urea. Further investigation via Western blotting, immunofluorescence and electron microscopy revealed autophagy and the Wnt/β-catenin pathway to be activated during hepatic differentiation of HPCs. Next, we found that inhibiting autophagy by downregulating Atg5 gene expression impaired hepatic differentiation of HPCs and inhibited activation of the Wnt/β-catenin pathway, which was rescued by overexpression of the β-catenin gene. Moreover, downregulating β-catenin gene expression without inhibiting autophagy still impeded the differentiation of HPCs. Finally, coimmunoprecipitation demonstrated that P62 forms a complex with phosphorylated glycogen synthase kinase 3 beta (pGSK3β). Third, in mouse CDE-induced liver injury, immunohistochemistry and immunofluorescence confirmed that downregulating Atg5 gene expression inhibited autophagy, thus impeding hepatic differentiation of HPCs and inhibiting activation of the Wnt/β-catenin pathway. As observed in vitro, overexpression of β-catenin rescued this phenomenon caused by autophagy inhibition, though decreasing β-catenin levels without autophagy inhibition still impeded HPC differentiation. We also found that HPCs differentiated into hepatocytes in human fibrotic liver tissue. Collectively, these results demonstrate that autophagy promotes HPC differentiation by regulating Wnt/β-catenin signaling. Our results are the first to identify a role for autophagy in promoting the hepatic differentiation of HPCs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagy promotes hepatic differentiation of hepatic progenitor cells by regulating the Wnt/β-catenin signaling pathway

Chen

et al. 2019

J Mol Hist

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“…38 Ductular reaction is commonly seen in liver diseases with chronic injury 63 and represents the expansion of DCs, also known as oval cells in rat and HPCs in some literatures. 63,64 Morphologically, DCs are small cells with a high nuclear/ cytosol ratio. Their origin is controversial and may represent different populations depending on the nature of injury.…”

Section: Role Of Hmgb1 In Ductular Reactionmentioning

confidence: 99%

“…They express several biliary cell markers, such as CK19, Sox9, and EpCAM, and hepatocyte markers, such as CK18 and albumin. 63,64 The driving force for the expansion of DCs is still far from clear. In autophagy-deficient livers, HMGB1 seems to be a major driving force.…”

Section: Role Of Hmgb1 In Ductular Reactionmentioning

confidence: 99%

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Homeostatic Role of Autophagy in Hepatocytes

et al. 2018

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Autophagy actively participates in the physiological process of the liver. While the direct effect of autophagy may be limited to the sequestration and degradation of a selective cargo, its overall impact can be broad, affecting many more physiological processes regulated by the particular cargo. This review will discuss two aspects of the importance of autophagy in the liver: metabolic regulation in response to feeding and starvation, and pathological consequences in the absence of autophagy. These two aspects illustrate the homeostatic functions of autophagy in the liver, one in a more direct fashion, regulating the cellular nutrient supply, and the other in a more indirect fashion, controlling the pathological signaling triggered by the abnormal accumulation of cargos. Remarkably, the hepatic pathology in autophagy-deficient livers does not seem different from that presented in other chronic liver diseases. Autophagy deficiency can be a model for the study of the relevant molecular mechanisms.

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