Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine
Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine
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DOI：
10.1016/s0002-9440(10)65574-5
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发表时间：
1998-07-01
影响因子：
6
通讯作者：
Shafritz, DA
中科院分区：
文献类型：
--
作者：
Laconi, E;Oren, R;Shafritz, DA
二肽基肽酶（DPP） IV+ Fischer 344大鼠的遗传标记肝细胞在联合逆转录酶（一种阻断肝细胞周期的吡罗里西啶生物碱）治疗和三分之二部分肝切除术后，移植到DPPIV-突变的Fischer 344大鼠的肝脏中。在雌性大鼠中，增殖的DPPIV+肝细胞簇在2周时很明显，每簇含有20至50个细胞，主要来自单个移植细胞，在1个月时每簇增加到数百个细胞，在2个月时每簇增加到1000至数千个细胞，占总肝细胞质量的40%至60%。这种水平的肝细胞替代保持不变长达1年，持续的实验进行。在雄性大鼠中，肝置换发生得更快更广泛，移植的肝细胞在2周时占肝细胞质量的10 - 15%，1个月时占40 - 50%，2个月时占90 - 95%，4个月时占98%，9个月时占99%。移植的肝细胞被整合到实质板中，表现出独特的肝脏生化功能，并完全重建了正常的肝小叶结构。在持续抑制常驻肝细胞的情况下，移植细胞的广泛增殖为研究肝脏再生的基本方面提供了一种新的通用模型，在慢性肝病和离体基因治疗中具有潜在的应用前景。
Genetically marked hepatocytes from dipeptidyl peptidase (DPP) IV+ Fischer 344 rats were transplanted into the liver of DPPIV- mutant Fischer 344 rats after a combined treatment with retrorsine, a pyrrolizidine alkaloid that blocks the hepatocyte cell cycle, and two-thirds partial hepatectomy. In female rats, clusters of proliferated DPPIV+ hepatocytes containing 20 to 50 cells/cluster, mostly derived from single transplanted cells, were evident at 2 weeks, increasing in size to hundreds of cells per cluster at 1 month and 1000 to several thousand cells per cluster at 2 months, representing 40 to 60% of total hepatocyte mass. This level of hepatocyte replacement remained constant for up to 1 year, the duration of experiments conducted. In male rats, Liver replacement occurred more rapidly and was more extensive, with transplanted hepatocytes representing 10 to 15% of hepatocyte mass at 2 weeks, 40 to 50% at 1 month, 90 to 95% at 2 months, 98% at 4 months, and 99% at 9 months. Transplanted hepatocytes were integrated into the parenchymal plates, exhibited unique hepatic biochemical functions, and fully reconstituted a normal hepatic lobular structure, The extensive proliferation of transplanted cells in this setting of persistent inhibition of resident hepatocytes represents a new general model to study basic aspects of liver repopulation with potential applications in chronic liver disease and ex vivo gene therapy.