Single Liver Lobe Repopulation with Wildtype Hepatocytes Using Regional Hepatic Irradiation Cures Jaundice in Gunn Rats

Hongchao Zhou, Xinyuan Dong, Rafi Kabarriti, Yong Chen, Yesim Avsar, Xia Wang, Jianqiang Ding, Laibin Liu, Ira J. Fox, Jayanta Roy-Chowdhury, Namita Roy-Chowdhury, Chandan Guha

Research output: Contribution to journalArticle

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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 (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. 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.

Original languageEnglish (US)
Article numbere46775
JournalPLoS One
Volume7
Issue number10
DOIs
StatePublished - Oct 16 2012

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Gunn Rats
jaundice
Jaundice
Liver
hepatocytes
Rats
Hepatocytes
irradiation
Irradiation
liver
rats
liver diseases
Liver Diseases
Transplantation
Radiation
Hepatocyte Growth Factor
Bilirubin
inherited metabolic diseases
hepatocyte growth factor
hyperbilirubinemia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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.

In: PLoS One, Vol. 7, No. 10, e46775, 16.10.2012.

Research output: Contribution to journalArticle

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. In: PLoS One. 2012 ; Vol. 7, No. 10.
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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 (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. 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.",
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AU - Zhou, Hongchao

AU - Dong, Xinyuan

AU - Kabarriti, Rafi

AU - Chen, Yong

AU - Avsar, Yesim

AU - Wang, Xia

AU - Ding, Jianqiang

AU - Liu, Laibin

AU - Fox, Ira J.

AU - Roy-Chowdhury, Jayanta

AU - Roy-Chowdhury, Namita

AU - Guha, Chandan

PY - 2012/10/16

Y1 - 2012/10/16

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AB - 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 (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. 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.

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