TY - JOUR
T1 - Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes
AU - Oren, Ran
AU - Dabeva, Mariana D.
AU - Karnezis, Anthony N.
AU - Petkov, Petko M.
AU - Rosencrantz, Richard
AU - Sandhu, Jaswinder P.
AU - Moss, Steven F.
AU - Wang, Shaobai
AU - Hurston, Ethel
AU - Laconi, Ezio
AU - Holt, Peter R.
AU - Thung, Swan N.
AU - Zhu, Liang
AU - Shafritz, David A.
PY - 1999
Y1 - 1999
N2 - Recently, we reported near-complete repopulation of the rat liver by transplanted hepatocytes using retrorsine (RS), a pyrrolizidine alkaloid that alkylates cellular DNA and blocks proliferation of resident hepatocytes, followed by transplantation of normal hepatocytes in conjunction with two- thirds partial hepatectomy (PH). Because two-thirds PH is not feasible for use in humans, in the present study, we evaluated the ability of thyroid hormone (triiodothyronine [T3]), a known hepatic mitogen, to stimulate liver repopulation in the retrorsine model. Because T3 initiates morphogenesis in amphibians through a process involving both cell proliferation and apoptosis, we also determined whether apoptosis might play a role in the mechanism of hepatocyte proliferation induced by T3. Following hepatocyte transplantation and repeated injections of T3, the number of transplanted hepatocytes in the liver of RS-pretreated animals increased progressively to repopulate 60% to 80% of parenchymal cell mass in 60 days. We show further that T3 treatment augments proliferation of normal hepatocytes, as evidenced by increased histone 3 mRNA and cyclin-dependent kinase 2 (cdk2) expression, and this is followed by apoptosis. These combined effects of T3 lead to selective proliferation of transplanted hepatocytes in RS-pretreated rats, while endogenous hepatocytes, which are blocked in their proliferative capacity by RS, mainly undergo apoptosis. Thus, T3 can replace PH in the RS-based rat liver repopulation model and therefore represents a significant advance in developing methods for hepatocyte transplantation.
AB - Recently, we reported near-complete repopulation of the rat liver by transplanted hepatocytes using retrorsine (RS), a pyrrolizidine alkaloid that alkylates cellular DNA and blocks proliferation of resident hepatocytes, followed by transplantation of normal hepatocytes in conjunction with two- thirds partial hepatectomy (PH). Because two-thirds PH is not feasible for use in humans, in the present study, we evaluated the ability of thyroid hormone (triiodothyronine [T3]), a known hepatic mitogen, to stimulate liver repopulation in the retrorsine model. Because T3 initiates morphogenesis in amphibians through a process involving both cell proliferation and apoptosis, we also determined whether apoptosis might play a role in the mechanism of hepatocyte proliferation induced by T3. Following hepatocyte transplantation and repeated injections of T3, the number of transplanted hepatocytes in the liver of RS-pretreated animals increased progressively to repopulate 60% to 80% of parenchymal cell mass in 60 days. We show further that T3 treatment augments proliferation of normal hepatocytes, as evidenced by increased histone 3 mRNA and cyclin-dependent kinase 2 (cdk2) expression, and this is followed by apoptosis. These combined effects of T3 lead to selective proliferation of transplanted hepatocytes in RS-pretreated rats, while endogenous hepatocytes, which are blocked in their proliferative capacity by RS, mainly undergo apoptosis. Thus, T3 can replace PH in the RS-based rat liver repopulation model and therefore represents a significant advance in developing methods for hepatocyte transplantation.
UR - http://www.scopus.com/inward/record.url?scp=0032853495&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032853495&partnerID=8YFLogxK
U2 - 10.1002/hep.510300418
DO - 10.1002/hep.510300418
M3 - Article
C2 - 10498641
AN - SCOPUS:0032853495
SN - 0270-9139
VL - 30
SP - 903
EP - 913
JO - Hepatology
JF - Hepatology
IS - 4
ER -