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Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats
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 pote...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473037/ https://www.ncbi.nlm.nih.gov/pubmed/23091601 http://dx.doi.org/10.1371/journal.pone.0046775 |
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author | Zhou, Hongchao Dong, Xinyuan Kabarriti, Rafi Chen, Yong Avsar, Yesim Wang, Xia Ding, Jianqiang Liu, Laibin Fox, Ira J. Roy-Chowdhury, Jayanta Roy-Chowdhury, Namita Guha, Chandan |
author_facet | Zhou, Hongchao Dong, Xinyuan Kabarriti, Rafi Chen, Yong Avsar, Yesim Wang, Xia Ding, Jianqiang Liu, Laibin Fox, Ira J. Roy-Chowdhury, Jayanta Roy-Chowdhury, Namita Guha, Chandan |
author_sort | Zhou, Hongchao |
collection | PubMed |
description | 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 (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. |
format | Online Article Text |
id | pubmed-3473037 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34730372012-10-22 Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats Zhou, Hongchao Dong, Xinyuan Kabarriti, Rafi Chen, Yong Avsar, Yesim Wang, Xia Ding, Jianqiang Liu, Laibin Fox, Ira J. Roy-Chowdhury, Jayanta Roy-Chowdhury, Namita Guha, Chandan PLoS One Research Article 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 (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. Public Library of Science 2012-10-16 /pmc/articles/PMC3473037/ /pubmed/23091601 http://dx.doi.org/10.1371/journal.pone.0046775 Text en © 2012 Zhou et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Zhou, Hongchao Dong, Xinyuan Kabarriti, Rafi Chen, Yong Avsar, Yesim Wang, Xia Ding, Jianqiang Liu, Laibin Fox, Ira J. Roy-Chowdhury, Jayanta Roy-Chowdhury, Namita Guha, Chandan Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats |
title | Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats |
title_full | Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats |
title_fullStr | Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats |
title_full_unstemmed | Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats |
title_short | Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats |
title_sort | single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in gunn rats |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473037/ https://www.ncbi.nlm.nih.gov/pubmed/23091601 http://dx.doi.org/10.1371/journal.pone.0046775 |
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