Studies of liver repopulation using the dipeptidyl peptidase IV-deficient rat and other rodent recipients: Cell size and structure relationships regulate capacity for increased transplanted hepatocyte mass in the liver lobule

Pankaj Rajvanhi, Andrew Kerr, Kuldeep K. Bhargava, Robert D. Burk, Sanjeev Gupta

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Abstract

The feasibility of liver repopulation with hepatocytes has been shown, although clinical applications demand significant hepatic replacement. To show whether portal vascular bed in large animals could accomodate a greater cell number, we analyzed liver repopulation in syngeneic Fischer 344 rats deficient in dipeptidyl peptidase IV. This system allowed localization of transplanted normal hepatocytes in liver or various ectopic sites, as well as dual studies for analysis of gene expression. Interestingly, the product of a dipeptidyl peptidase IV substrate inactivated bile canalicular adenosine triphosphatase (ATPase) activity in normal but not in dipeptidyl peptidase IV-deficient rats, which allowed localization of dipeptidyl peptidase IV-deficient hepatocytes in normal rat liver for additional reversed transplantation systems. Further studies with genetically marked cells showed that because of the size difference between hepatocytes and portal vein radicles, intrasplenically transplanted cells were distributed in periportal areas (zone 1) in mice, whereas in larger animals (rats or rabbits) cells were also distributed downstream to midlobular (zone 2) or perivenous (zone 3) areas. Transplantation of an escalating number of hepatocytes showed that adult rats tolerated intrasplenic injection of a large cell number in single sessions (up to 1 × 108, ∼10% to 15% of the host hepatocyte mass). Morphometric analysis of recipient livers showed survival of a significantly greater cell number with incorporation in host liver plates. At 4 weeks, transplantation of 2 × 107 hepatocytes into adult rats led to survival of 1.4 ± 1.0 × 106 transplanted cells/cm3 liver, whereas after transplantation of 5 × 107 cells or 7.5 × 107 cells, the number of surviving transplanted cells in the liver significantly increased to 4.1 ± 1.4 × 106 transplanted cells/cm3 liver (mean, 2.9 fold; P < .003) and 5.5 ± 1.3 × 106 transplanted cells/cm3 liver (mean, 3.9-fold; P < .003), respectively. When cells were injected in greater numbers, transplanted hepatocytes retained normal function and produced more serum albumin or hepatitis B surface antigen in deficient hosts. These data indicate the feasibility in larger animals of significant liver repopulation with hepatocyte transplantation. Use of dipeptidyl peptidase IV-deficient rats should help further analysis of mechanisms in liver repopulation.

Original languageEnglish (US)
Pages (from-to)482-496
Number of pages15
JournalHepatology
Volume23
Issue number3
StatePublished - 1996

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Dipeptidyl Peptidase 4
Cell Size
Hepatocytes
Rodentia
Liver
Transplantation
Cell Count
Inbred F344 Rats
Hepatitis B Surface Antigens
Portal Vein
Bile
Serum Albumin
Blood Vessels
Adenosine Triphosphatases

ASJC Scopus subject areas

  • Hepatology

Cite this

@article{ecb87b94412248d6b788e80b49631057,
title = "Studies of liver repopulation using the dipeptidyl peptidase IV-deficient rat and other rodent recipients: Cell size and structure relationships regulate capacity for increased transplanted hepatocyte mass in the liver lobule",
abstract = "The feasibility of liver repopulation with hepatocytes has been shown, although clinical applications demand significant hepatic replacement. To show whether portal vascular bed in large animals could accomodate a greater cell number, we analyzed liver repopulation in syngeneic Fischer 344 rats deficient in dipeptidyl peptidase IV. This system allowed localization of transplanted normal hepatocytes in liver or various ectopic sites, as well as dual studies for analysis of gene expression. Interestingly, the product of a dipeptidyl peptidase IV substrate inactivated bile canalicular adenosine triphosphatase (ATPase) activity in normal but not in dipeptidyl peptidase IV-deficient rats, which allowed localization of dipeptidyl peptidase IV-deficient hepatocytes in normal rat liver for additional reversed transplantation systems. Further studies with genetically marked cells showed that because of the size difference between hepatocytes and portal vein radicles, intrasplenically transplanted cells were distributed in periportal areas (zone 1) in mice, whereas in larger animals (rats or rabbits) cells were also distributed downstream to midlobular (zone 2) or perivenous (zone 3) areas. Transplantation of an escalating number of hepatocytes showed that adult rats tolerated intrasplenic injection of a large cell number in single sessions (up to 1 × 108, ∼10{\%} to 15{\%} of the host hepatocyte mass). Morphometric analysis of recipient livers showed survival of a significantly greater cell number with incorporation in host liver plates. At 4 weeks, transplantation of 2 × 107 hepatocytes into adult rats led to survival of 1.4 ± 1.0 × 106 transplanted cells/cm3 liver, whereas after transplantation of 5 × 107 cells or 7.5 × 107 cells, the number of surviving transplanted cells in the liver significantly increased to 4.1 ± 1.4 × 106 transplanted cells/cm3 liver (mean, 2.9 fold; P < .003) and 5.5 ± 1.3 × 106 transplanted cells/cm3 liver (mean, 3.9-fold; P < .003), respectively. When cells were injected in greater numbers, transplanted hepatocytes retained normal function and produced more serum albumin or hepatitis B surface antigen in deficient hosts. These data indicate the feasibility in larger animals of significant liver repopulation with hepatocyte transplantation. Use of dipeptidyl peptidase IV-deficient rats should help further analysis of mechanisms in liver repopulation.",
author = "Pankaj Rajvanhi and Andrew Kerr and Bhargava, {Kuldeep K.} and Burk, {Robert D.} and Sanjeev Gupta",
year = "1996",
language = "English (US)",
volume = "23",
pages = "482--496",
journal = "Hepatology",
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T1 - Studies of liver repopulation using the dipeptidyl peptidase IV-deficient rat and other rodent recipients

T2 - Cell size and structure relationships regulate capacity for increased transplanted hepatocyte mass in the liver lobule

AU - Rajvanhi, Pankaj

AU - Kerr, Andrew

AU - Bhargava, Kuldeep K.

AU - Burk, Robert D.

AU - Gupta, Sanjeev

PY - 1996

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N2 - The feasibility of liver repopulation with hepatocytes has been shown, although clinical applications demand significant hepatic replacement. To show whether portal vascular bed in large animals could accomodate a greater cell number, we analyzed liver repopulation in syngeneic Fischer 344 rats deficient in dipeptidyl peptidase IV. This system allowed localization of transplanted normal hepatocytes in liver or various ectopic sites, as well as dual studies for analysis of gene expression. Interestingly, the product of a dipeptidyl peptidase IV substrate inactivated bile canalicular adenosine triphosphatase (ATPase) activity in normal but not in dipeptidyl peptidase IV-deficient rats, which allowed localization of dipeptidyl peptidase IV-deficient hepatocytes in normal rat liver for additional reversed transplantation systems. Further studies with genetically marked cells showed that because of the size difference between hepatocytes and portal vein radicles, intrasplenically transplanted cells were distributed in periportal areas (zone 1) in mice, whereas in larger animals (rats or rabbits) cells were also distributed downstream to midlobular (zone 2) or perivenous (zone 3) areas. Transplantation of an escalating number of hepatocytes showed that adult rats tolerated intrasplenic injection of a large cell number in single sessions (up to 1 × 108, ∼10% to 15% of the host hepatocyte mass). Morphometric analysis of recipient livers showed survival of a significantly greater cell number with incorporation in host liver plates. At 4 weeks, transplantation of 2 × 107 hepatocytes into adult rats led to survival of 1.4 ± 1.0 × 106 transplanted cells/cm3 liver, whereas after transplantation of 5 × 107 cells or 7.5 × 107 cells, the number of surviving transplanted cells in the liver significantly increased to 4.1 ± 1.4 × 106 transplanted cells/cm3 liver (mean, 2.9 fold; P < .003) and 5.5 ± 1.3 × 106 transplanted cells/cm3 liver (mean, 3.9-fold; P < .003), respectively. When cells were injected in greater numbers, transplanted hepatocytes retained normal function and produced more serum albumin or hepatitis B surface antigen in deficient hosts. These data indicate the feasibility in larger animals of significant liver repopulation with hepatocyte transplantation. Use of dipeptidyl peptidase IV-deficient rats should help further analysis of mechanisms in liver repopulation.

AB - The feasibility of liver repopulation with hepatocytes has been shown, although clinical applications demand significant hepatic replacement. To show whether portal vascular bed in large animals could accomodate a greater cell number, we analyzed liver repopulation in syngeneic Fischer 344 rats deficient in dipeptidyl peptidase IV. This system allowed localization of transplanted normal hepatocytes in liver or various ectopic sites, as well as dual studies for analysis of gene expression. Interestingly, the product of a dipeptidyl peptidase IV substrate inactivated bile canalicular adenosine triphosphatase (ATPase) activity in normal but not in dipeptidyl peptidase IV-deficient rats, which allowed localization of dipeptidyl peptidase IV-deficient hepatocytes in normal rat liver for additional reversed transplantation systems. Further studies with genetically marked cells showed that because of the size difference between hepatocytes and portal vein radicles, intrasplenically transplanted cells were distributed in periportal areas (zone 1) in mice, whereas in larger animals (rats or rabbits) cells were also distributed downstream to midlobular (zone 2) or perivenous (zone 3) areas. Transplantation of an escalating number of hepatocytes showed that adult rats tolerated intrasplenic injection of a large cell number in single sessions (up to 1 × 108, ∼10% to 15% of the host hepatocyte mass). Morphometric analysis of recipient livers showed survival of a significantly greater cell number with incorporation in host liver plates. At 4 weeks, transplantation of 2 × 107 hepatocytes into adult rats led to survival of 1.4 ± 1.0 × 106 transplanted cells/cm3 liver, whereas after transplantation of 5 × 107 cells or 7.5 × 107 cells, the number of surviving transplanted cells in the liver significantly increased to 4.1 ± 1.4 × 106 transplanted cells/cm3 liver (mean, 2.9 fold; P < .003) and 5.5 ± 1.3 × 106 transplanted cells/cm3 liver (mean, 3.9-fold; P < .003), respectively. When cells were injected in greater numbers, transplanted hepatocytes retained normal function and produced more serum albumin or hepatitis B surface antigen in deficient hosts. These data indicate the feasibility in larger animals of significant liver repopulation with hepatocyte transplantation. Use of dipeptidyl peptidase IV-deficient rats should help further analysis of mechanisms in liver repopulation.

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