Hepatocyte Growth Factor Promotes Liver Regeneration Induced By Transfusion Of Bone Marrow Mononuclear Cells In A Murine Acute Liver Failure Model

Bone marrow mononuclear cells (BMMCs) transplantation represents a potential treatment to enhance hepatic regeneration after acute or chronic liver failure. BMMCs can differentiate into hepatic cells in vitro and in vivo following certain induction or stimulation procedures, thus demonstrating their potential for hepatocyte regeneration after perfusion of hibernating cells. BMMCs transplantation may therefore provide an alternative treatment for liver failure, in addition to classic liver transplantation. Novel strategies have been recently proposed to booster the therapeutic potential of stem cell treatment, often involving co-administration of certain growth factors or cytokines. Hepatocyte growth factor (HGF) may have angiogenic effect, and together with vascular endothelia growth factor, HGF may facilitate the development hematopoietic progenitor cells. Recently, HGF has been demonstrated to stimulate engraftment of BMMCs to vascular endothelia cells in injured organs. Further, HGF has shown great potential as an anti-apoptosis, anti-inflammation, and anti-fibrosis agent. These cellular effects of HGF may be highly beneficial in the treatment of liver failure. Xue et al demonstrated that HGF gene therapy stimulates liver cell proliferation and promote liver functional recovery after resection of cirrhotic livers. Recently a research group from Japan reported that HGF can promote remodeling of murine liver fibrosis and accelerate recruitment of bone marrow-derived cells into the liver, which may involves increased expression of stromal cell-derived factor-1 (SDF-1). We have recently shown that BMMCs transplantation help liver regeneration following CC14 injury. The present study was set to explore whether HGF co-administration may further the beneficial effect of BMMCs transplantation in the recovery following acute liver damage.Objective: Bone marrow mononuclear cells (BMMCs) transplantation has been shown to facilitate tissue/organ regeneration/repair. BMMCs transplantation may be a potential therapy for acute liver failure, and its effect might be further improved. Hepatocyte growth factor promotes (HGF) plays an important role in liver cell development, and may ameliorate hepatic fibrosis or cirrhosis in animal models. We therefore explore a potential synergistic effect of co-application of HGF and BMMCs in liver regeneration following carbon tetrachloride (CC14) induced acute hepatic injury. Methods:We established a murine acute liver failure model induced by CC14 administration. The effect of BMMCs transplantation in combination with HGF was studied among 4 groups of animals receiving transfused with PKH26-labeled BMMCs (5×106) and HGF (50 ng/kg.d×7 days) (BMMCs+HGF group), BMMCs only, HGF only and saline solution (0.9% NaCl) alone, by biochemical measurements of liver enzymes and quantitative image analysis for PKH26 labeling, proliferating cell nuclear antigen (PCNA) and albumin expression 4 weeks after marrow cell transplantation. Results:PKH26-labeled BMMCs were detected in transplanted mouse livers, most of which expressed PCNA. PCNA and albumin expressions were increased significantly in BMMCs+HGF groups compared with the other 3 groups. Liver function, reflected by serum aminotransferase activity, was also improved in the BMMCs+HGF relative to other groups. Conclusions:Data from the present study appear to suggest that BMMCs transplantation combined with HGF administration exhibits synergistic beneficial effect on improving functional and histological liver recovery in a mouse model of acute liver failure.