Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis

Abstract

Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to be beneficial for the treatment of liver fibrosis. Here, we investigated the use of genetically engineered MSCs that overexpress hepatocyte growth factor (HGF) as a means to improve their therapeutic effect in liver fibrosis. Liver fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. HGF-secreting MSCs (MSCs/HGF) were prepared by transducing MSCs with an adenovirus carrying HGF-encoding cDNA. MSCs or MSCs/HGF were injected directly into the spleen of fibrotic rats. Tissue fibrosis was assessed by histological analysis 12 days after stem cell injection. Although treatment with MSCs reduced fibrosis, treatment with MSCs/HGF produced a more significant reduction and was associated with elevated HGF levels in the portal vein. Collagen levels in the liver extract were decreased after MSC/HGF therapy, suggesting recovery from fibrosis. Furthermore, liver function was improved in animals receiving MSCs/HGF, indicating that MSC/HGF therapy resulted not only in reduction of liver fibrosis but also in improvement of hepatocyte function. Assessment of cell and biochemical parameters revealed that mRNA levels of the fibrogenic cytokines PDGF-bb and TGF-β1 were significantly decreased after MSC/HGF therapy. Subsequent to the decrease in collagen, expression of matrix metalloprotease-9 (MMP-9), MMP-13, MMP-14 and urokinase-type plasminogen activator was augmented following MSC/HGF, whereas tissue inhibitor of metalloprotease-1 (TIMP-1) expression was reduced. In conclusion, therapy with MSCs/HGF resulted in an improved therapeutic effect compared with MSCs alone, probably because of the anti-fibrotic activity of HGF. Thus, MSC/HGF represents a promising approach toward a cell therapy for liver fibrosis.

Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives

“…Moreover, proinflammatory factors were shown to induce HGF expression levels in MSCs [114]. Forced expression of HGF in MSCs was able to further ameliorate liver fibrosis when compared to MSCs-alone treatment in a rat dimethylnitrosamine model [115].…”

Hepatocyte Growth Factor Facilitates Esophageal Mucosal Repair and Inhibits the Submucosal Fibrosis in a Rat Model of Esophageal Ulcer

“…The mechanisms were probably due to its effects on promoting the expression of profibrogenic cytokines and influencing the MMP/TIMP balance [48]. The possibility of the anti-fibrotic activity of HGF in the liver was indicated [49]. In our study, the expression of TIMP-1, TIMP-2, MMP-2 and MMP-9 mRNA was significantly suppressed in the esophagus by HGF treatment on day 7 after inducing the esophageal ulcer; however, this may simply have been the result of normal wound healing [41].…”

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

“…HGF‐overexpressing MSCs also decreased the levels of tissue inhibitor of metalloprotease‐1 (TIMP‐1) and the fibrogenic cytokines platelet‐derived growth factor beta polypeptide b (PDGF‐bb) and TGF‐β1 but increased the expression of MMP‐9, MMP‐13, MMP‐14 and urokinase‐type plasminogen activator in fibrotic liver tissues. Thus, HGF‐secreting MSCs obviously reduced liver fibrosis in rats after decreasing collagen deposition and improving liver function …”