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首页> 外文期刊>Human gene therapy. Clinical development >A Systematic Approach to the Establishment and Characterization of Endothelial Progenitor Cells for Gene Therapy
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A Systematic Approach to the Establishment and Characterization of Endothelial Progenitor Cells for Gene Therapy

机译：用于基因治疗的内皮祖细胞的建立和表征的系统方法

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It has been recently demonstrated that endothelial progenitor cells (EPCs) have increasing potential for gene therapy or regenerative cell therapy for cardiovascular diseases and cancer. However, current therapies involving EPCs are inefficient because of the very low level of EPCs in the available sources, for example, in blood. One solution is to derive in vitro an expanded population of EPCs from circulation. In addition, EPCs like other progenitor cells have an intrinsic predisposition of differentiating into mature cell types, for example, mature endothelial cells; therefore, establishing a sufficient amount of EPCs alongside maintaining the EPC characteristic phenotype during genetic modification and long-term culture presents a significant challenge to the field of gene and cell therapies. In this study, we have systematically investigated EPCs from different sources and used multiple parameters, including cell surface markers and a tubule formation assay to identify factors that influence the establishment, characteristics, and vector transduction capability of EPCs. Our results show the considerable promise, as well as certain limitations in the establishment and manipulation of genetically modified EPCs for gene therapy. While obtaining high transduction efficiency and robust in vitro tubule formation of EPCs using lentiviral vectors, we also observed that lentiviral vector transduction significantly altered EPC phenotype as demonstrated by an increased percentage of CD34~+ progenitor cells and increased expression of adhesion molecule CD144 (VE-cadherin). Taking account of the increased expression of CD144 reported in cancer patients, the altered expression of EPC-related markers, for example, VE-cadherin and the enrichment of CD34~+ cells, after vector transduction indicates the importance of extensive characterization and vigorous safety control of genetically modified EPCs before they are accepted for clinical use.
机译：最近已经证明，内皮祖细胞（EPC）具有用于心血管疾病和癌症的基因治疗或再生细胞治疗的潜力越来越大。然而，由于可用来源例如血液中的EPC水平非常低，目前涉及EPC的疗法效率低下。一种解决方案是在体外从循环中获得更多的EPC。此外，EPC与其他祖细胞一样，具有分化成成熟细胞类型（例如成熟内皮细胞）的固有倾向。因此，在遗传修饰和长期培养过程中建立足够数量的EPC并保持EPC特征表型，对基因和细胞治疗领域提出了重大挑战。在这项研究中，我们已经系统地研究了来自不同来源的EPC，并使用了多个参数，包括细胞表面标志物和肾小管形成测定法，以识别影响EPC的建立，特征和载体转导能力的因素。我们的结果显示出可观的前景，以及在建立和处理用于基因治疗的转基因EPC方面的某些局限性。在使用慢病毒载体获得高转导效率和稳定的体外EPC小管形成的同时，我们还观察到慢病毒载体转导显着改变了EPC表型，这通过CD34〜+祖细胞百分比的增加和粘附分子CD144（VE-钙粘蛋白）。考虑到癌症患者中CD144表达的增加，载体转导后EPC相关标志物（例如VE-cadherin）的表达变化和CD34〜+细胞的富集表明广泛表征和严格安全控制的重要性转基因的EPC在被接受用于临床之前。

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