Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes.
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 [T(3)]), a known hepatic mitogen, to stimulate liver repopulation in the retrorsine model. Because T(3) 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 T(3). Following hepatocyte transplantation and repeated injections of T(3), 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 T(3) 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 T(3) 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, T(3) can replace PH in the RS-based rat liver repopulation model and therefore represents a significant advance in developing methods for hepatocyte transplantation.
Oren
R
R
The Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Dabeva
M D
MD
Karnezis
A N
AN
Petkov
P M
PM
Rosencrantz
R
R
Sandhu
J P
JP
Moss
S F
SF
Wang
S
S
Hurston
E
E
Laconi
E
E
Holt
P R
PR
Thung
S N
SN
Zhu
L
L
Shafritz
D A
DA
D000818:Animals; D017209:Apoptosis; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000502:physiology; D017690:Cell Transplantation; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006657:Histones / Q000235:genetics; D017403:In Situ Hybridization; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D008934:Mitogens / Q000494:pharmacology; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014284:Triiodothyronine / Q000494:pharmacology / Q000502:physiology*
D006657:Histones; D008934:Mitogens; D011763:Pyrrolizidine Alkaloids; D012333:RNA, Messenger; D014284:Triiodothyronine; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C003300:retrorsine