Oren R, Dabeva M D, Karnezis A N, Petkov P M, Rosencrantz R, Sandhu J P, Moss S F, Wang S, Hurston E, Laconi E, Holt P R, Thung S N, Zhu L, Shafritz D A
The Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Hepatology. 1999 Oct;30(4):903-13. doi: 10.1002/hep.510300418.
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.
最近，我们报道了使用倒千里光碱（RS）对大鼠肝脏进行移植肝细胞的近乎完全再填充，RS是一种吡咯里西啶生物碱，可使细胞DNA烷基化并阻断驻留肝细胞的增殖，随后将正常肝细胞与三分之二部分肝切除术（PH）联合移植。由于三分之二PH在人类中不可行，在本研究中，我们评估了甲状腺激素（三碘甲状腺原氨酸[T(3)]）（一种已知的肝有丝分裂原）在倒千里光碱模型中刺激肝脏再填充的能力。由于T(3)通过涉及细胞增殖和凋亡的过程启动两栖动物的形态发生，我们还确定了凋亡是否可能在T(3)诱导的肝细胞增殖机制中起作用。在肝细胞移植和重复注射T(3)后，RS预处理动物肝脏中移植肝细胞的数量逐渐增加，在60天内重新填充实质细胞质量的60%至80%。我们进一步表明，T(3)处理增强了正常肝细胞的增殖，组蛋白3 mRNA和细胞周期蛋白依赖性激酶2（cdk2）表达增加证明了这一点，随后发生凋亡。T(3)的这些联合作用导致RS预处理大鼠中移植肝细胞的选择性增殖，而被RS阻断增殖能力的内源性肝细胞主要发生凋亡。因此，T(3)可以在基于RS的大鼠肝脏再填充模型中替代PH，因此代表了肝细胞移植方法开发的重大进展。
