Lentiviral vectors mediate efficient and stable gene transfer in adult neural stem cells in vivo
Lentiviral vectors mediate efficient and stable gene transfer in adult neural stem cells in vivo
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DOI：
10.1089/hum.2006.17.635
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发表时间：
2006-06-01
影响因子：
4.2
通讯作者：
Debyser, Zeger
中科院分区：
文献类型：
--
作者：
Geraerts, Martine;Eggermont, Kristel;Debyser, Zeger
成人神经发生的调节可能为各种脑部疾病提供新的治疗策略。在成年哺乳动物大脑中，侧脑室的室下区（SVZ）是连续神经发生的区域。慢病毒载体可以稳定地整合到分裂和非分裂细胞中，而逆转录病毒载体则只能整合到分裂细胞中。我们比较了它们将基因转移到静止和缓慢分裂的干细胞以及更快分裂的祖细胞中的潜力。与逆转录病毒载体相比，将慢病毒载体立体定向注射到成年小鼠的 SVZ 中，可以在具有未成熟 B 型细胞和迁移前体细胞特征的细胞中实现高效、长期的标记基因表达。沿着头端迁移流迁移和分化后，同侧嗅球中表达增强型绿色荧光蛋白（eGFP）的颗粒和球周中间神经元的数量随着时间的推移而增加。此外，SVZ 中 eGFP 标记的神经元祖细胞的数量随着时间的推移而增加。通过心室内注射慢病毒载体，我们可以限制基因转移至室管膜细胞和 B 型星形胶质细胞样干细胞。总之，在基础研究和治疗应用中，慢病毒载体在脑室下区干细胞的有效长期体内标记方面优于逆转录病毒载体。
Modulation of adult neurogenesis may offer new therapeutic strategies for various brain disorders. In the adult mammalian brain the subventricular zone (SVZ) of the lateral ventricle is a region of continuous neurogenesis. Lentiviral vectors stably integrate into dividing and nondividing cells, in contrast to retroviral vectors, which integrate only into dividing cells. We compared their potential for gene transfer into both quiescent and slowly dividing stem cells as well as into more rapidly dividing progenitor cells. In contrast to retroviral vectors, stereotactic injection of lentiviral vectors into the SVZ of adult mice resulted in efficient and long-term marker gene expression in cells with characteristics of both immature type B cells and migrating precursor cells. After migration along the rostral migratory stream and differentiation, the number of enhanced green fluorescent protein (eGFP)-expressing granular and periglomerular interneurons increased over time in the ipsilateral olfactory bulb. Moreover, the number of eGFP-labeled neuronal progenitor cells in the SVZ increased over time. By intraventricular injection of lentiviral vectors we could restrict gene transfer to ependymal cells and type B astroglial-like stem cells. In conclusion, lentiviral vectors surpass retroviral vectors in efficient long-term in vivo marking of subventricular zone stem cells for basic research and therapeutic applications.