Normal hepatocytes correct serum bilirubin after repopulation of gunn rat liver subjected to irradiation/partial resection

Chandan Guha, Bhupesh Parashar, Niloy J. Deb, Madhur K. Garg, Giridhar R. Gorla, Anupam Singh, Namita Roy-Chowdhury, Bhadrasain Vikram, Jayanta Roy-Chowdhury

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)354-362
Number of pages9
JournalHepatology
Volume36
Issue number2
DOIs
StatePublished - 2002

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Gunn Rats
Bilirubin
Hepatocytes
Hepatectomy
Liver
Serum
Transplantation
Liver Diseases
Glucuronosyltransferase
Uridine
Metabolic Diseases
Enzyme Assays

ASJC Scopus subject areas

  • Hepatology

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Normal hepatocytes correct serum bilirubin after repopulation of gunn rat liver subjected to irradiation/partial resection. / Guha, Chandan; Parashar, Bhupesh; Deb, Niloy J.; Garg, Madhur K.; Gorla, Giridhar R.; Singh, Anupam; Roy-Chowdhury, Namita; Vikram, Bhadrasain; Roy-Chowdhury, Jayanta.

In: Hepatology, Vol. 36, No. 2, 2002, p. 354-362.

Research output: Contribution to journalArticle

Guha, Chandan ; Parashar, Bhupesh ; Deb, Niloy J. ; Garg, Madhur K. ; Gorla, Giridhar R. ; Singh, Anupam ; Roy-Chowdhury, Namita ; Vikram, Bhadrasain ; Roy-Chowdhury, Jayanta. / Normal hepatocytes correct serum bilirubin after repopulation of gunn rat liver subjected to irradiation/partial resection. In: Hepatology. 2002 ; Vol. 36, No. 2. pp. 354-362.
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abstract = "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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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 K.

AU - Gorla, Giridhar R.

AU - Singh, Anupam

AU - Roy-Chowdhury, Namita

AU - Vikram, Bhadrasain

AU - Roy-Chowdhury, Jayanta

PY - 2002

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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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