Transforming growth factor β induces expression of connective tissue growth factor in hepatic progenitor cells through Smad independent signaling

Abstract

Hepatic progenitor cells (HPCs) are activated in the chronic liver injury and are found to participate in the progression of liver fibrosis, while the precise role of HPCs in liver fibrosis remains largely elusive. In this study, by immunostaining of human liver sections, we confirmed that HPCs were activated in the cirrhotic liver and secreted transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF), both of which were important inducers of liver fibrosis. Besides, we used HPC cell lines LE/6 and WB-F344 as in vitro models and found that TGF-β induced secretion of CTGF in HPCs. Moreover, TGF-β signaling was intracrine activated and contributed to autonomous secretion of CTGF in HPCs. Furthermore, we found that TGF-β induced expression of CTGF was not mediated by TGF-β activated Smad signaling but mediated by TGF-β activated Erk, JNK and p38 MAPK signaling. Taken together, our results provide evidence for the role of HPCs in liver fibrosis and suggest that the production of CTGF by TGF-β activated MAPK signaling in HPCs may be a therapeutic target of liver fibrosis.

Keywords: CTGF; Connective tissue growth factor; ECM; EMT; Erk; HPCs; HSCs; Hepatic progenitor cells; IFN-γ; Intracrine signaling; JNK; MAPK; PI3K; Smad-independent signaling; TGF-β; Transforming growth factor β; c-Jun N-terminal kinase; connective tissue growth factor; epithelial–mesenchymal transition; extracellular matrix; extracellular signal-regulated kinase; hepatic progenitor cells; hepatic stellate cells; interferon-γ; mitogen activated protein kinase; phosphatidylinositol 3-kinase; shRNA; small hairpin RNA; transforming growth factor β.