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1.
Cell Res ; 29(1): 8-22, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30361550

RESUMO

The study of pathophysiological mechanisms in human liver disease has been constrained by the inability to expand primary hepatocytes in vitro while maintaining proliferative capacity and metabolic function. We and others have previously shown that mouse mature hepatocytes can be converted to liver progenitor-like cells in vitro with defined chemical factors. Here we describe a protocol achieving efficient conversion of human primary hepatocytes into liver progenitor-like cells (HepLPCs) through delivery of developmentally relevant cues, including NAD + -dependent deacetylase SIRT1 signaling. These HepLPCs could be expanded significantly during in vitro passage. The expanded cells can readily be converted back into metabolically functional hepatocytes in vitro and upon transplantation in vivo. Under three-dimensional culture conditions, differentiated cells generated from HepLPCs regained the ability to support infection or reactivation of hepatitis B virus (HBV). Our work demonstrates the utility of the conversion between hepatocyte and liver progenitor-like cells for studying HBV biology and antiviral therapies. These findings will facilitate the study of liver diseases and regenerative medicine.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B/patologia , Hepatócitos , Fígado/patologia , Células-Tronco , Animais , Diferenciação Celular , Células Cultivadas , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Camundongos , Sirtuína 1/metabolismo , Células-Tronco/citologia , Células-Tronco/patologia
2.
Cell Death Dis ; 9(5): 575, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29760381

RESUMO

It is well known that induction of hepatocyte senescence could inhibit the development of hepatocellular carcinoma (HCC). Until now, it is still unclear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury, on the contrary did not result into hepatocyte senescence, but led to a significant incidence of HCC instead. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. Meanwhile, immune surveillance, especially the activations of macrophages, was activated after re-induction of senescence by severe acute liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with activating immune surveillance and a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Senescência Celular , Hepatócitos/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/lesões , Fígado/metabolismo , Doença Aguda , Animais , Carcinoma Hepatocelular/patologia , Hepatócitos/patologia , Fígado/patologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Knockout
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