Synergistic growth factors enhance rat liver proliferation and enable retroviral gene transfer via a peripheral vein
Synergistic growth factors enhance rat liver proliferation and enable retroviral gene transfer via a peripheral vein
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DOI：
10.1016/s0016-5085(00)70266-6
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发表时间：
2000-03-01
期刊：
影响因子：
29.4
通讯作者：
Hodgson, HJF
中科院分区：
文献类型：
--
作者：
Forbes, SJ;Themis, M;Hodgson, HJF
背景与目的：反映肝细胞功能异常的遗传性疾病有可能通过基因治疗治愈。逆转录病毒载体提供了永久纠正这种状况的可能性。这些载体通常需要细胞分裂发生，以允许前病毒进入细胞核，在许多实验方案中通过部分肝切除术启动。方法：采用三碘甲腺原氨酸（T3）和角质细胞生长因子（KGF）诱导大鼠肝细胞增殖。门静脉内和外周给药的影响，编码的Lac Z基因在生长因子诱导的肝脏增生的逆转录病毒进行了分析。结果：T3可诱导肝细胞中层增殖，而KGF诱导后，肝细胞增殖更为弥散。最佳浓度的T3和KGF协同作用，诱导61%的肝细胞在完整的肝脏中的增殖。这使得在体内肝细胞转导，导致基因表达高达7.3%的肝细胞后，门静脉内逆转录病毒载体给药和7.1%后，外周静脉给药。结论：T3和KGF协同诱导未损伤肝细胞增殖。在生长因子诱导的增殖波期间，可以通过外周静脉系统用整合载体简单地转导肝脏。
Background & Aims: Genetic diseases reflecting abnormal hepatocyte function are potentially curable through gene therapy. Retroviral vectors offer the potential for permanent correction of such conditions. These vectors generally require cell division to occur to allow provirus:entry into the nucleus, initiated in many experimental protocols by partial hepatectomy. We have explored methods to improve the efficiency of retroviral gene transfer that avoid the need for liver damage, Methods: Triiodothyronine (T3) and keratinocyte growth factor (KGF) were used to induce hepatic proliferation in rats. The effects of intraportal and peripheral administration of a modified retrovirus that encoded the Lac Z gene during growth factor-induced liver hyperplasia were analyzed. Results: T3 Initiated hepatocyte proliferation midzonally; after KGF, proliferation was more diffuse. Optimal concentrations of T3 and KGF acted synergistically to induce proliferation in 61% of hepatocytes in the intact liver. This enabled in vivo hepatocyte transduction, leading to gene expression by up to 7.3% of hepatocytes after intraportal retroviral vector administration and 7.1% after peripheral venous administration. Conclusions: T3 and KGF act synergistically to induce hepatocyte proliferation in undamaged liver. The liver can be simply transduced with integrating vectors via the peripheral venous system during a wave of growth factor-induced proliferation.