RESUMO
Hepatic progenitor cells (HPCs) are bipotential stem cells that can differentiate into mature hepatocytes or biliary epithelial cells (BECs). They are thought to be involved in repair of liver injury and the incidence of hepatic carcinoma. Their physiology is closely associated with the microenvironment where they reside. Lipopolysaccharide (LPS), an important component of the hepatic pathological microenvironment, is stored in the liver and affects many types of cells in various hepatosis. HPCs may also be influenced by LPS. In this paper, mouse ED13.5 E-cadherin+ foetal liver cells were isolated as mouse hepatic progenitor cells (mHPCs). Proliferation of mHPCs was promoted under LPS conditions both in vivo and in vitro. Moreover, LPS enhanced colony formation ability of mHPCs, and blocked them differentiation into mature hepatocytes and formation of a bile duct-liked structure. More importantly, long-term treatment with LPS promoted tumorigenesis of mHPCs in nude mice. Thus, we conclude that LPS may promote aberrant proliferation of mHPCs and restrict their normal differentiation. Long-term exposure of mHPCs to LPS increased the risk of tumour formation. These data provide insight into the links between LPS, HPCs fate, and tumorigenesis, and present novel insight into the relationship between HPCs and their microenvironment.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Hepatócitos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Neoplasias Hepáticas Experimentais/induzido quimicamente , Fígado/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Animais , Caderinas/metabolismo , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células Cultivadas , Relação Dose-Resposta a Droga , Idade Gestacional , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatócitos/transplante , Fígado/embriologia , Fígado/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Fenótipo , Piridinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco , Transplante de Células-Tronco , Células-Tronco/metabolismo , Células-Tronco/patologia , Fatores de Tempo , Microambiente TumoralRESUMO
Normally, hepatic progenitor cells (HPCs) are activated and differentiate into hepatocytes or bile ductular cells to repair liver damage during liver injury. However, it remains controversial whether the abnormal differentiation of HPCs occurs under abnormal conditions. Lipopolysaccharide (LPS), a component of the microenvironment, promotes liver fibrosis. In the present study, HPCs promoted liver fibrosis in rats following carbon tetrachloride (CCl4) treatment. Meanwhile, the LPS level in the portal vein was elevated and played a primary role in the fate of HPCs. In vitro, LPS inhibited the hepatobiliary differentiation of HPCs. Concurrently, HPCs co-cultured with LPS for 2 weeks showed a tendency to differentiate into myofibroblasts (MFs). Thus, we conclude that LPS promotes the aberrant differentiation of HPCs into MFs as a third type of descendant. This study provides insight into a novel differentiation fate of HPCs in their microenvironment, and could thus lead to the development of HPCs for treatment methods in liver fibrosis.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Proteínas Hedgehog/genética , Lipopolissacarídeos/farmacologia , Cirrose Hepática/genética , Transplante de Células-Tronco , Células-Tronco/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Tetracloreto de Carbono , Diferenciação Celular , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Regulação da Expressão Gênica , Proteínas Hedgehog/agonistas , Proteínas Hedgehog/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Lipopolissacarídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Ratos , Ratos Endogâmicos F344 , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Proteína GLI1 em Dedos de Zinco/agonistas , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína Gli3 com Dedos de Zinco/agonistas , Proteína Gli3 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/metabolismoRESUMO
Hepatocyte nuclear factor-1beta plays an important role in the development and progression of liver cancer. In recent years, the expression of HNF-1ß has been reported to be associated with risk for a variety of cancers. The purpose of this study is to investigate whether the expression of HNF-1ß promotes the malignancy of HCC and its mechanism. We retrospectively investigated the expression of HNF-1ß in 90 patients with hepatocellular carcinoma and found that the high expression of HNF-1ß indicated poor prognosis. We overexpressed HNF-1ß in liver cancer cell lines and found the expression of liver progenitor cell markers and stemness were upregulated. The invasion ability and epithelial-mesenchymal transition (EMT)-associated genes were also significantly higher in liver cancer cells overexpressing HNF-1ß than in the control group. A mechanistic study suggested the activation of the Notch signalling pathway probably plays a key role downstream of HNF-1ß. More importantly, HNF-1ß promoted tumourigenesis of HCC cells in vivo. In conclusion, high expression of HNF-1ß not only promoted the de-differentiation of HCC cells into liver cancer stem cells through activating the Notch pathway but also enhanced the invasive potential of HCC cells and EMT occurrence, which would contribute to the enhancement of cell migration and invasion.