Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats Hongchao Zhou 1 , Xinyuan Dong 1 , Rafi Kabarriti1, Yong Chen 2 , Yesim Avsar2, Xia Wang 2 , Jianqiang Ding2, Laibin Liu1, Ira J. Fox3, Jayanta Roy-Chowdhury2, Namita Roy-Chowdhury2*, Chandan Guha1* 1 Departments of Radiation Oncology and Pathology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America, 2 Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America, 3 Department of Surgery, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC and McGowan Institute of Regenerative Medicine, Pittsburgh, Pennsylvania, United States of America Abstract Background and Aims: Preparative 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. Methods: Hepatocytes (107) isolated from wildtype F344 rats or Wistar-RHA rats were engrafted into the livers of congeneic dipeptidylpeptidase IV deficient (DPPIV2) 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. Results: 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. In Gunn rats receiving median lobe HIR, serum bilirubin declined from pretreatment levels of 5.1760.78 mg/dl to 0.9660.30 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. Conclusions: As 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. Citation: Zhou H, Dong X, Kabarriti R, Chen Y, Avsar Y, et al. (2012) Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats. PLoS ONE 7(10): e46775. doi:10.1371/journal.pone.0046775 Editor: Simon Afford, University of Birmingham, United Kingdom Received May 8, 2012; Accepted September 5, 2012; Published October 16, 2012 Copyright: 2012 Zhou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health grants: RO1 DK 46057 and RO1 DK 67440, NY Stem CO24346 (to JRC); DK RO1 079017 (NRC), Oxalosis and Hyperoxaluria Foundation (to NRC); R01 DK64670 and R21/R33 CA121051 (to CG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: cguha@montefiore.org (CG); Namita.Roychowdhury@Einstein.YU.edu (NR-C) Introduction Hepatocyte transplantation has been used as an alternative to whole liver transplantation for amelioration of metabolic deficien- cies in a number of patients with various inherited liver-based metabolic disorders [1–7]. While these studies have demonstrated the safety and feasibility of this procedure, the number of hepatocytes that could be engrafted in single procedures was insufficient for complete cure of these diseases [8–11]. In the majority of inherited metabolic diseases of the liver, the longevity of the mutant hepatocytes is not significantly limited. Because the liver to body weight ratio is tightly regulated by physiological mechanisms, simple metabolic stimulation does not lead to extensive proliferation of the donor cells. Inhibition of the mitotic potential of the host cells provides a competitive proliferative advantage to the donor cells [12,13], allowing massive prolifera- tion of the donor cells, which replace significant fractions of the host hepatocyte mass in response to mitotic stimuli. Since the chemical methods used by many investigators for this purpose are probably not suitable for translation to clinical application, we have explored hepatic irradiation (HIR) to inhibit the growth of the host hepatocytes [14,15]. Our results in rodent and non- human primate models show that preparative whole liver HIR PLOS ONE | www.plosone.org 1 October 2012 | Volume 7 | Issue 10 | e46775