Reconstruction of cirrhotic liver by means of extracellular matrix remodeling and differential stimulation of stem cells.

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The purpose of the present study was to clarify the role of bone marrow-derived multipotent stem cells in the reconstructing process of cirrhotic livers during gene therapy with hepatocyte growth factor(HGF) cCDNA. [Methods]C57BL/6J mice received CCl_4(2.0ml/kg p.o.) for 6 weeks, developing liver cirrhosis. After irradiation of 900cGy, these animals underwent transplantation with bone marrow cells derived from LacZ transgenic mice. After the transplantation, some of the recipients were injected with HGF cDNA encapsulated in HVJ-liposome(200μg/body i.m.) once a week for 4 weeks. Control animal received empty HVJ-liposome. CCl_4 administration was continued once a week during this period. In these animals, recruitment of LacZ-positive bone marrow-derived cells into the liver was investigated immunohistochemically. Expression of c-Met/HGF receptor on the cell surface of bone marrow cells was also examined. [Results]Gene therapy with HGF cDNA effectively attenuated liver cirrhosis in the mice. During the reconstructing process of the cirrhotic livers, most of the donor derived LacZ-positive cells differentiated into the endothelial cells or sinusoidal endothelial cells. Small part of the LacZ-positive cells also differentiated into Kupffer cells, but not into hepatocyte, oval cells, or hepatic sttelate cells. Expression of c-Met was detected immunohistochemically on some of the bone marrow cells. [Conclusion]These results suggest that reconstruction of cirrhotic liver is efficiently carried out in combination of hepatic tissue-derived and bone-marrow-derived stem cell differentiation. HGF possibly accelerates differentiation of these stem cells into liver-constituting cells.