Fas/CD95 pathway induces mouse liver regeneration and allows for highly efficient retrovirus-mediated gene transfer
Fas/CD95 pathway induces mouse liver regeneration and allows for highly efficient retrovirus-mediated gene transfer
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DOI：
10.1053/jhep.2001.20678
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发表时间：
2001-01-01
期刊：
影响因子：
13.5
通讯作者：
Gilgenkrantz, H
中科院分区：
文献类型：
--
作者：
Guidotti, JE;Mallet, VO;Gilgenkrantz, H
已提出将基因稳定转移到肝细胞中以补偿影响肝功能的遗传缺陷，或将扩散因子输送到循环中。这一策略可以使用逆转录病毒载体来实现；然而，细胞分裂必须发生。我们描述了一种简单的繁殖方法，能够以受控的方式诱导肝细胞复制，从而实现有效的体内逆转录病毒肝转导，适用于人类遗传性疾病的小鼠模型。该方法基于肝脏通过 Fas/CD95 途径对细胞凋亡的敏感性。我们发现，单次Fas激动剂抗体（JO2）注射后4天，肝细胞复制发生，其强度与诱导的肝细胞溶解水平相关。这种治疗能够实现体内肝转导，其效率也与肝细胞溶解水平相关。当肝细胞复制期间静脉注射重组逆转录病毒载体时，15.4%+/-1.7%的肝细胞被转导，最高可达32.5%。
Stable gene transfer into hepatocytes has been proposed to compensate for genetic deficiencies that affect liver function, or to deliver diffusible factors into the circulation. This strategy can be achieved using retroviral vectors; however, cell division must occur. We describe a simple and reproductive method that enables the induction of hepatocyte replication in a controlled fashion, thus allowing an efficient in vivo retroviral liver transduction that is applicable to mouse models of human genetic disorders. The approach is based on liver susceptibility to apoptosis via the Fas/CD95 pathway. We show that, 4 days following a single Fas agonist antibody (JO2) injection, hepatocyte replication occurs, the intensity of which is correlated with the level of the induced hepatic cytolysis, This treatment enables in vivo liver transduction, and its efficiency also correlates with the level of hepatic cytolysis. When recombinant retroviral vectors were infused intravenously during the period of hepatocyte replication, 15.4% +/- 1.7% of the hepatocytes were transduced, reaching up to 32.5%.