Abstract
Cirrhosis is the terminal stage of hepatic diseases and is prone to develop into hepatocyte carcinoma. Increasing evidence suggests that the transplantation of dental pulp stem cells (DPSCs) may promote recovery from cirrhosis, but the key regulatory mechanisms involved remain to be determined. In this study, we overexpressed human hepatocyte growth factor (hHGF) in primary rat DPSCs and evaluated the effects of HGF overexpression on the biological behaviors and therapeutic efficacy of grafted DPSCs in cirrhosis. Liver cirrhosis was induced via the intraperitoneal injection of CCl4 twice weekly for 12 weeks and was verified through histopathological and serological assays. HGF was overexpressed in DPSCs via transduction with a hHGF-lentiviral vector and confirmed based on the elevated expression and secretion of HGF. The HGF-overexpressing DPSCs were transplanted into rats intravenously. The HGF-overexpressing DPSCs showed increased survival and hepatogenic differentiation in host liver tissue at 6 weeks after grafting. They also exhibited a significantly greater repair potential in relation to cirrhosis pathology and impaired liver function than did DPSCs expressing HGF at physiological levels. Our study may provide an experimental basis for the development of novel methods for the treatment of liver cirrhosis in clinical practice.
Highlights
Cirrhosis, characterized by diffuse degeneration and the death of hepatocytes, followed by nodular regeneration, extensive fibrosis and the consequent collapse of the normal liver architecture, is the terminal stage of a variety of chronic liver diseases, resulting in irreversible impaired liver function, portal hypertension and the potential to develop into hepatocellular carcinoma[1,2]
These results indicated that the major histopathological and serological changes of liver cirrhosis had emerged in CCl4-treated rats
We investigated the impacts of human Hepatocyte growth factor (HGF) (hHGF) overexpression on the in vivo biological behaviors and the therapeutic efficacy of Dental pulp stem cells (DPSCs) for the treatment of liver cirrhosis
Summary
Cirrhosis, characterized by diffuse degeneration and the death of hepatocytes, followed by nodular regeneration, extensive fibrosis and the consequent collapse of the normal liver architecture, is the terminal stage of a variety of chronic liver diseases, resulting in irreversible impaired liver function, portal hypertension and the potential to develop into hepatocellular carcinoma[1,2]. Mesenchymal stem cell (MSC) transplantation, which has shown notable potential for repairing hepatic architecture and function in preclinical studies, may represent a prospective therapy for liver fibrosis[6]. The determinant induction of hepatic differentiation of DPSCs and the therapeutic efficacy of DPSC grafting for cirrhosis remain poorly understood. HGF has been verified to show anti-fibrotic activity in both the onset and progression of liver fibrosis/cirrhosis[17,18]. In the present study, we overexpressed human HGF (hHGF) in rat-derived primary DPSCs through the transduction of a hHGF-expressing lentiviral vector and evaluated the effects of elevated HGF expression on the survival, fate determination and regenerative capacity of grafted DPSCs in a rat model of cirrhosis to provide an experimental basis for the development of a novel anti-cirrhosis therapy
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