TY - JOUR
T1 - Normal hepatocytes correct serum bilirubin after repopulation of Gunn rat liver subjected to irradiation/partial resection
AU - Guha, Chandan
AU - Parashar, Bhupesh
AU - Deb, Niloy J.
AU - Garg, Madhur
AU - Gorla, Giridhar R.
AU - Singh, Anupam
AU - Roy-Chowdhury, Namita
AU - Vikram, Bhadrasain
AU - Roy-Chowdhury, Jayanta
N1 - Funding Information:
Abbreviations: HT, hepatocyte transplantation; PH, partial hepatectomy; HIR, hepatic irradiation; UGT1A1, bilirubin-uridine 5′-diphosphoglucuronate glucu-ronosyltransferase; RHA, Roman High Avoidance; BrdU, 5-bromo-2′-deoxyuridine. From the Departments of 1Radiation Oncology, 3Medicine, 4Pathology, and 5Molecular Genetics and 2The Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY. Received February 17, 2002; accepted May 6, 2002. Supported in part by National Institutes of Health grants RO1-DK 46057 (to J.R.-C.) and RO1-DK 39137 (to N.R.-C.), Liver Research Core Center grant DK-P30-41296 (Director, David A. Shafritz), and American Cancer Society grant RPG-00-066-01-CCE (to C.G.). Presented at the 1999 annual meeting of the American Association for the Study of Liver Diseases in Dallas, TX. Address reprint requests to: Chandan Guha, M.D., Ph.D., Department of Radiation Oncology, Montefiore Medical Center, 111 East 210 St., Bronx, NY 10467. E-mail: cguha@montefiore.org; fax: 718-231-5064. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3602-0012$35.00/0 doi:10.1053/jhep.2002.34516
PY - 2002
Y1 - 2002
N2 - The treatment of inherited metabolic liver diseases by hepatocyte transplantation (HT) would be greatly facilitated if the transplanted normal hepatocytes could be induced to proliferate preferentially over the host liver cells. We hypothesized that preparative hepatic irradiation (HIR) should inhibit host hepatocyte proliferation in response to partial hepatectomy (PH). Normal nonirradiated hepatocytes transplanted in this setting should have a selective growth advantage over the host liver cells and should progressively repopulate the liver. To test this hypothesis, we transplanted 5 million hepatocytes from normal Wistar-Roman High Avoidance (RHA) rats into the livers of congeneic bilirubin-uridine 5′-diphosphoglucuronate glucuronosyltransferase (UGT1A1)-deficient jaundiced Gunn rats by intrasplenic injection after one of the following treatments: (1) 68% PH, (2) HIR (50 Gy), or (3) HIR + PH. In rats receiving either PH or HIR alone before HT, serum bilirubin concentrations declined by 25% to 30% in 28 weeks. In contrast, serum bilirubin levels were normalized completely in rats receiving HIR + PH before HT. Massive repopulation of the Gunn rat liver by the UGT1A1-positive Wistar-RHA hepatocytes was shown by UGT1A1 enzyme assay, immunoblot analysis, and immunohistochemical staining of the recipient liver. High-performance liquid chromatography analysis of the bile collected from Gunn rats 5 months after PH, HIR, and HT showed normalization of the pigment profile, with bilirubin diglucuronide and monoglucuronide as the predominant pigments. In conclusion, a preparative regimen of HIR + PH results in massive repopulation of the liver with functionally normal transplanted hepatocytes, resulting in complete correction of a metabolic deficiency. Noninvasive strategies to replace PH for providing proliferative stimuli to the transplanted cells should make this regimen valuable in augmenting the effects of HT for the treatment of liver diseases.
AB - The treatment of inherited metabolic liver diseases by hepatocyte transplantation (HT) would be greatly facilitated if the transplanted normal hepatocytes could be induced to proliferate preferentially over the host liver cells. We hypothesized that preparative hepatic irradiation (HIR) should inhibit host hepatocyte proliferation in response to partial hepatectomy (PH). Normal nonirradiated hepatocytes transplanted in this setting should have a selective growth advantage over the host liver cells and should progressively repopulate the liver. To test this hypothesis, we transplanted 5 million hepatocytes from normal Wistar-Roman High Avoidance (RHA) rats into the livers of congeneic bilirubin-uridine 5′-diphosphoglucuronate glucuronosyltransferase (UGT1A1)-deficient jaundiced Gunn rats by intrasplenic injection after one of the following treatments: (1) 68% PH, (2) HIR (50 Gy), or (3) HIR + PH. In rats receiving either PH or HIR alone before HT, serum bilirubin concentrations declined by 25% to 30% in 28 weeks. In contrast, serum bilirubin levels were normalized completely in rats receiving HIR + PH before HT. Massive repopulation of the Gunn rat liver by the UGT1A1-positive Wistar-RHA hepatocytes was shown by UGT1A1 enzyme assay, immunoblot analysis, and immunohistochemical staining of the recipient liver. High-performance liquid chromatography analysis of the bile collected from Gunn rats 5 months after PH, HIR, and HT showed normalization of the pigment profile, with bilirubin diglucuronide and monoglucuronide as the predominant pigments. In conclusion, a preparative regimen of HIR + PH results in massive repopulation of the liver with functionally normal transplanted hepatocytes, resulting in complete correction of a metabolic deficiency. Noninvasive strategies to replace PH for providing proliferative stimuli to the transplanted cells should make this regimen valuable in augmenting the effects of HT for the treatment of liver diseases.
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U2 - 10.1053/jhep.2002.34516
DO - 10.1053/jhep.2002.34516
M3 - Article
C2 - 12143043
AN - SCOPUS:0036322035
SN - 0270-9139
VL - 36
SP - 354
EP - 362
JO - Hepatology
JF - Hepatology
IS - 2
ER -