Human liver stem cells improve liver injury in a model of fulminant liver failure.

INTRODUCTION: Liver transplantation is currently the only effective therapy for fulminant liver failure, but its use is limited by the scarcity of organs for transplantation, high costs and lifelong immunosuppression. Here we investigated whether human liver stem cells (HLSCs) protect from death in a lethal model of fulminant liver failure induced by intraperitoneal injection of D-galactosamine and lipopolysaccharide in SCID mice. We showed that injection of HLSCs HLSC-conditioned medium (CM) significantly attenuates mouse mortality in mice in this model. RESULTS: Histopathological analysis of liver tissue showed reduction of liver apoptosis and enhancement of liver regeneration. By optical imaging, we observed a preferential localization of labeled HLSCs within the liver. HLSCs were detected by immunohistochemistry in large liver vessel (at 24 hours) and the liver parenchyma (after day 3). FISH analysis with the human pan-centromeric probe showed that positive cells were cytokeratin-negative at 24 hours. Co-expression of cytokeratin and human chromosome was observed at 7 and, lesser extent, at 21 days. HLSC-derived CM mimicked the effect of HLSCsin vivo. Composition analysis of the HLSC-CM revealed the presence of growth factors and cytokines with liver regenerative properties. In vitro experiments showed that HLSC-CM protected human hepatocytes from apoptosis and enhanced their proliferation. CONCLUSION: These data suggest that fulminant liver failure may potentially benefit from treatment with HLSCs or HLSC-CM.