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.
Highlights
Hepatocyte transplantation has been used as an alternative to whole liver transplantation for amelioration of metabolic deficiencies in a number of patients with various inherited liver-based metabolic disorders [1,2,3,4,5,6,7]
Three months after hepatocyte transplantation in DPPIV2 rats, 30–60% of the recipient hepatocytes were replaced by donor cells in the irradiated lobe, but not in the nonirradiated lobes
To determine the effect of targeted hepatic irradiation (HIR) to the liver, DPPIV+ Fisher 344 (F344) hepatocytes were transplanted into congeneic DPPIV2 rat livers that had been subjected to preparative HIR of one half of the median lobe only
Summary
Hepatocyte transplantation has been used as an alternative to whole liver transplantation for amelioration of metabolic deficiencies in a number of patients with various inherited liver-based metabolic disorders [1,2,3,4,5,6,7]. HIR allows the engrafted cells to respond more efficiently to mitotic stimuli, such as partial hepatectomy or expression of hepatic growth factor (HGF), than the host hepatocytes. This leads to extensive repopulation of the liver with complete correction of the metabolic defect in the uridinediphosphoglucuronate glucuronosyltransferase 1A1 (ugt1a1)-deficient Gunn rat model of Crigler-Najjar syndrome type 1 (CN1) [16] and a mouse model of primary hyperoxaluria type 1 (PH1) [17]. We test the hypothesis that repopulation of selected liver lobes by regional HIR should be sufficient to correct some inherited metabolic disorders
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