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

Abstract

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 show that injection of HLSCs and of HLSC-conditioned medium (CM) significantly attenuates mouse mortality in this model. 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 vessels (at 24 hours) and in the liver parenchyma (after day 3). Fluorescence in situ hybridization analysis with the human pan-centromeric probe showed that positive cells were cytokeratin-negative at 24 hours. Coexpression of cytokeratin and human chromosome was observed at 7 and, to a lesser extent, at 21 days. HLSC-derived CM mimicked the effect of HLSCs in 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. (HEPATOLOGY 2013;57:311-319)

Acetaminophen hepatotoxicity: an updated review

“…A 1999 case series of 18 patients showed no effects of hepatocyte transplantation on clinical outcome in ALF. More clinical trials are currently in progress, and murine studies with human hepatocyte transplantation are promising (Dhawan et al 2010;Herrera et al 2013;Struecker et al 2014). …”

Recellularization of Rat Liver Scaffolds by Human Liver Stem Cells

“…HLSC are easily obtainable from small surgical samples or from biopsies of human adult liver. 14,16 In addition, these cells exhibit a great proliferation potential, remain stable for over 30 culture passages, without chromosomal aberrations, and a good manufacturing protocol.…”

“…They express several mesenchymal, but not hematopoietic, stem cell markers and express embryonic markers such as alpha-fetoprotein (AFP), nestin, nanog, sox2, Musashi1, Oct 3/4, and pax2. 14,16 Moreover HLSC express albumin, AFP and cytokeratin 18 (CK18) supporting their partial hepatic commitment. 14 The effectiveness in restoring the hepatic mass and function has been also described.…”

“…14 The effectiveness in restoring the hepatic mass and function has been also described. 16 Indeed, HLSC are able to enhance survival and to improve the tissue recovery in SCID mice with fulminant liver failure. These characteristics make the HLSC potential candidates for generation of functional hepatocytes to be used in regenerative medicine.…”

Reply

“…1 We did not explore the reason for this difference. Dong et al suggest that natural killer (NK) cells may limit survival of human BM-MSCs in severe combined immune deficiency (SCID) mice.…”