TY - JOUR
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
Y1 - 1996
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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U2 - 10.1002/hep.510230313
DO - 10.1002/hep.510230313
M3 - Article
C2 - 8617428
AN - SCOPUS:0030009209
SN - 0270-9139
VL - 23
SP - 482
EP - 496
JO - Hepatology
JF - Hepatology
IS - 3
ER -