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首页> 外文期刊>Cell discovery. >Uniparental disomy of the entire X chromosome in Turner syndrome patient-specific induced pluripotent stem cells
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Uniparental disomy of the entire X chromosome in Turner syndrome patient-specific induced pluripotent stem cells

机译：Turner综合征患者特异性诱导多能干细胞中整个X染色体的单亲二体性

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The human induced pluripotent stem cell (iPSC) technique promises to provide an unlimited, reliable source of genetically matched pluripotent cells for personalized therapy and disease modeling. Recently, it is observed that cells with ring chromosomes 13 or 17 autonomously correct the defects via compensatory uniparental disomy during cellular reprogramming to iPSCs. This breakthrough finding suggests a potential therapeutic approach to repair large-scale chromosomal aberrations. However, due to the scarceness of ring chromosome samples, the reproducibility of this approach in different individuals is not carefully evaluated yet. Moreover, the underlying mechanism and the applicability to other types of chromosomal aberrations remain unknown. Here we generated iPSCs from four 45,X chorionic villous fibroblast lines and found that only one reprogrammed line acquired 46,XX karyotype via uniparental disomy of the entire X chromosome. The karyotype correction was reproducible in the same cell line by either retroviral or episomal reprogramming. The karyotype-corrected iPSCs were subject to X chromosome inactivation and obtained better colony morphology and higher proliferation rate than other uncorrected ones. Further transcriptomic comparison among the fibroblast lines identified a distinct expression pattern of cell cycle regulators in the uncorrectable ones. These findings demonstrate that the iPSC technique holds the potential to correct X monosomy, but the correction rate is very low, probably due to differential regulation of cell cycle genes between individuals. Our data strongly suggest that more systematic investigations are needed before defining the iPSC technique as a novel means of chromosome therapy.
机译：人类诱导多能干细胞（iPSC）技术有望为个性化治疗和疾病建模提供无限，可靠的遗传匹配多能细胞来源。最近，观察到在将细胞重编程为iPSC的过程中，具有环状13号或17号染色​​体的细胞可通过补偿性单亲二体性来自主纠正缺陷。这一突破性发现提示修复大范围染色体畸变的潜在治疗方法。但是，由于环状染色体样品的稀缺性，尚未对这种方法在不同个体中的可重复性进行仔细评估。而且，其潜在机理和对其他类型的染色体畸变的适用性仍然未知。在这里，我们从四个45，X绒毛膜绒毛成纤维细胞系中产生了iPSC，发现只有一个重编程的细胞系通过整个X染色体的单亲二体性获得了46，XX核型。通过逆转录病毒或附加型重编程，核型校正可在同一细胞系中重现。核型校正的iPSCs经历了X染色体失活，比其他未校正的iPSC具有更好的菌落形态和更高的增殖率。成纤维细胞系之间的进一步转录组学比较确定了不可校正的细胞周期调节子的独特表达模式。这些发现表明，iPSC技术具有纠正X单体性的潜力，但纠正率非常低，这可能是由于个体之间细胞周期基因的差异性调控所致。我们的数据强烈表明，在将iPSC技术定义为一种新的染色体治疗手段之前，需要进行更系统的研究。

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