Abstract
Hepatocyte transplantation holds great promise as an alternative to orthotopic organ transplantation in the treatment of liver diseases. However, obtaining clinically meaningful levels of liver repopulation has not been achieved because the mechanisms regulating hepatocyte proliferation in recipient livers have not yet been well characterized. In the mouse model of Hereditary Tyrosinemia Type I, the fumarylacetoacetate hydrolase-deficient (Fah−/−) mouse, we found gradually increasing expression level of insulin-like growth factor 2 (IGF2) in the hepatocytes of host livers. Similarly, high levels of IGF2 were found in the livers of patients with deficient FAH activity. Recombinant IGF2 directly promotes proliferation of primary hepatocytes in vitro. Inhibition on IGF2 expression through the interruption of PI3K/Akt and MAPK pathways significantly reduced the level of liver repopulation in Fah−/− mice. Interestingly, treatment with IGF2 before hepatocyte transplantation generally improved the amount of liver repopulation seen in various mice models of liver injury. Altogether, these findings underscore the underlying mechanisms of therapeutic liver repopulation in Fah−/− mice, and indicate that IGF2 is a potential hepatocyte mitogen for liver cell transplantation therapies.
Highlights
Cell transplantation therapies have the potential to treat a wide variety of diseases by making up for tissue defects
insulin-like growth factor 2 (IGF2) expression is induced during liver injury in Fah−/− mice The hepatocytes of Fah−/− mice undergo injury upon termination of NTBC administration
In line with previous reports[14], we found that only a few scattered hepatocytes become positive for the assay of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nicked labeling (TUNEL), and only a few small necrotic foci were found in the livers of Fah−/− mice off NTBC for up to 4 weeks (Fig. 1a, b)
Summary
Cell transplantation therapies have the potential to treat a wide variety of diseases by making up for tissue defects. Several obstacles still hinder the widespread clinical application of cell therapies. The difficulty in achieving sufficient donor cell engraftment into host tissues is one major technical obstacle[1]. Hepatocyte transplantation therapy has been performed in clinical trials as an alternative to orthotopic liver transplantation for some types of genetic diseases of the liver and for acute liver failure[2,3]. The extent of liver engraftment and repopulation after hepatocyte. The second is to supply or regulate hepatic mitogens as well as cell-cycle regulators to drive proliferation of the transplanted hepatocytes in recipient livers[8,9]. Among the rodent models for liver repopulation, the mouse model of Hereditary Tyrosinemia Type I (HT1), the fumarylacetoacetate hydrolasedeficient (Fah−/−) mouse, is the best example of repopulation of the liver, reaching >90% of total hepatocyte replacement by transplanted wild-type hepatocytes[10,11]
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