Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats

Abstract

Background and AimsPreparative hepatic irradiation (HIR), together with mitotic stimulation of hepatocytes, permits extensive hepatic repopulation by transplanted hepatocytes in rats and mice. However, whole liver HIR is associated with radiation-induced liver disease (RILD), which limits its potential therapeutic application. In clinical experience, restricting HIR to a fraction of the liver reduces the susceptibility to RILD. Here we test the hypothesis that repopulation of selected liver lobes by regional HIR should be sufficient to correct some inherited metabolic disorders.MethodsHepatocytes (107) isolated from wildtype F344 rats or Wistar-RHA rats were engrafted into the livers of congeneic dipeptidylpeptidase IV deficient (DPPIV−) rats or uridinediphosphoglucuronateglucuronosyltransferase-1A1-deficient jaundiced Gunn rats respectively by intrasplenic injection 24 hr after HIR (50 Gy) targeted to the median lobe, or median plus left liver lobes. An adenovector expressing hepatocyte growth factor (1011 particles) was injected intravenously 24 hr after transplantation.ResultsThree months after hepatocyte transplantation in DPPIV− rats, 30–60% of the recipient hepatocytes were replaced by donor cells in the irradiated lobe, but not in the nonirradiated lobes. In Gunn rats receiving median lobe HIR, serum bilirubin declined from pretreatment levels of 5.17±0.78 mg/dl to 0.96±0.30 mg/dl in 8 weeks and remained at this level throughout the 16 week observation period. A similar effect was observed in the group, receiving median plus left lobe irradiation.ConclusionsAs little as 20% repopulation of 30% of the liver volume was sufficient to correct hyperbilirubinemia in Gunn rats, highlighting the potential of regiospecific HIR in hepatocyte transplantation-based therapy of inherited metabolic liver diseases.

Construction of liver tissue in vivo with preparative partial hepatic irradiation and growth stimulus: investigations of less invasive techniques and progenitor cells

“…We measured the levels of serum HGF, which is known as a strong stimulator for hepatocytes growth. Although supplying HGF via an adenovirus vector was demonstrated to induce proliferation of transplanted hepatocytes (10,11,14), PVBL did not increase the levels of HGF, as observed in the clinical PVE study (16). Liver regeneration is regulated by an orchestrated and complex response, involving not only HGF, but also various kinds of mediators.…”

Translational Animal Models for Regenerative Medicine Research

“…Consequently, the challenge was to provide a competitive advantage to the donor hepatocytes. An approach that has had success in a rat model has been to irradiate part of the recipient liver [79]. This increases engraftment of the donor hepatocytes and provides evidence of a benefit.…”

Translational Regenerative Medicine—Hepatic Systems

“…In the treatment of metabolic disorders, there is a need to suppress the proliferation of the host hepatocytes, in order for the donor cells to properly repopulate the liver. Preparative irradiation of the host liver [80][81][82], or suppression of host-hepatocyte proliferation through drug treatments [83], has been researched in preclinical trials to enhance the preferential proliferation of the transplanted cells. Technological improvements are also needed in the ability of researchers to quantify the number of donor versus host cells posttransplantation, in order to properly evaluate the success of these treatments.…”