Hedgehog signaling pathway regulates liver regeneration in the Fah-/- knockout mice model xenografted by human hepatocytes

Background: The aim of this study is to evaluates the hypothesis that Hh pathway activation occurs in the Fah-/- Nod/Scid mice model and plays a role in regulating liver regeneration after functional human hepatocytes xenograft. Methods: Fah-/- Nod/Scid mice were established in Shandong Cancer Hospital affiliated to Shandong University. Xeno-regeneration of Fah-/- Nod/Scid mice livers was then transplanted by human hepatocytes. Hh signaling pathway associated factors were detected by RT-PCR and western blot. All statistical calculations were carried out using the SPSS.16.0 software. Results: Fah-/- mice were healthy and reproduced normally while treated with NTBC. NTBC-OFF Fah-/- mice with HHT gradually gained weight by six weeks after human hepatocyte transplantation. NTBC-OFF Fah-/- mice causes a progressive increase in ALT, AST, GGT and AP, which were used to monitor hepatocyte inflammation. However, liver function in NTBC-OFF Fah Fah-/- mice with HHT returned to normal. Hedgehog pathway activation and Hh-target genes were enhanced follows human hepatocytes transplantation which indicated liver regeneration associated closely with Hh signaling pathway. Moreover, Hh signaling was inhibited by cyclopamine after HHT. Conclusions: The current study provides novel evidence that Hedgehog signaling pathway regulation is required for optimal regeneration of NTBC OFF Fah-/- mice with HHT.