Introduction of Exogenous HSV-TK Suicide Gene Increases Safety of Keratinocyte-Derived Induced Pluripotent Stem Cells by Providing Genetic "Emergency Exit" Switch.
Introduction of Exogenous HSV-TK Suicide Gene Increases Safety of Keratinocyte-Derived Induced Pluripotent Stem Cells by Providing Genetic "Emergency Exit" Switch.
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DOI：
10.3390/ijms19010197
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发表时间：
2018-01-09
影响因子：
5.6
通讯作者：
Majka M
中科院分区：
文献类型：
--
作者：
Sułkowski M;Konieczny P;Chlebanowska P;Majka M
自2006年发明以来，诱导多能干细胞（iPS）仍然是再生医学的一大希望，可以规避与胚胎干细胞（ES）研究相关的伦理问题。iPS细胞可以以患者特异性方式产生，作为各种细胞类型的无限来源，用于体外药物筛选，发育生物学研究和再生用途。iPS细胞具有分化成所有三个初级胚层细胞的能力，具有形成畸胎瘤肿瘤的高潜力。这仍然是它们的主要缺点和危险，在解决之前，这阻碍了iPS细胞在临床中的利用。本研究通过引入外源性自杀基因单纯疱疹病毒胸苷激酶（HSV-TK）来提高iPS细胞的安全性。它的表达导致转基因细胞对前药更昔洛韦（GCV）的特异性脆弱性。我们表明，表达HSV-TK的细胞可以在体外和体内用低剂量的GCV以高特异性和效率被根除。所描述的策略通过产生"紧急出口"开关来增加iPS细胞在未来临床应用中的安全性，所述"紧急出口"开关允许在移植细胞发生故障的情况下根除移植细胞。
Since their invention in 2006, induced Pluripotent Stem (iPS) cells remain a great promise for regenerative medicine circumventing the ethical issues linked to Embryonic Stem (ES) cell research. iPS cells can be generated in a patient-specific manner as an unlimited source of various cell types for in vitro drug screening, developmental biology studies and regenerative use. Having the capacity of differentiating into the cells of all three primary germ layers, iPS cells have high potential to form teratoma tumors. This remains their main disadvantage and hazard which, until resolved, prevents utilization of iPS cells in clinic. Here, we present an approach for increasing iPS cells safety by introducing genetic modification—exogenous suicide gene Herpes Simplex Virus Thymidine Kinase (HSV-TK). Its expression results in specific vulnerability of genetically modified cells to prodrug—ganciclovir (GCV). We show that HSV-TK expressing cells can be eradicated both in vitro and in vivo with high specificity and efficiency with low doses of GCV. Described strategy increases iPS cells safety for future clinical applications by generating “emergency exit” switch allowing eradication of transplanted cells in case of their malfunction.
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