title: Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in Gunn rats.
abstract: OBJECTIVE
  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 (10(7)) 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 (10(11) particles) was injected intravenously 24 hr after transplantation.
  
  
  RESULTS
  Three 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.
  
  
  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.
authors.affiliation: Departments of Radiation Oncology and Pathology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Hongchao
authors.initials: H
authors.lastname: Zhou
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Dong
authors.forename: Rafi
authors.initials: R
authors.lastname: Kabarriti
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Yesim
authors.initials: Y
authors.lastname: Avsar
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Ding
authors.forename: Laibin
authors.initials: L
authors.lastname: Liu
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Fox
authors.forename: Jayanta
authors.initials: J
authors.lastname: Roy-Chowdhury
authors.forename: Namita
authors.initials: N
authors.lastname: Roy-Chowdhury
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001663:Bilirubin / Q000097:blood / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000528:radiation effects / Q000637:transplantation*; D007565:Jaundice / Q000378:metabolism / Q000628:therapy*; D008099:Liver / Q000378:metabolism / Q000528:radiation effects / Q000601:surgery; D008115:Liver Regeneration / Q000528:radiation effects; D008297:Male; D051381:Rats; D055647:Rats, Transgenic; D019172:Transplantation Conditioning; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D018819:Dipeptidyl Peptidase 4; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme