Uniparental disomy of the entire X chromosome in Turner syndrome patient-specific induced pluripotent stem cells.
Uniparental disomy of the entire X chromosome in Turner syndrome patient-specific induced pluripotent stem cells.
复制标题
特纳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
DOI：
10.1038/celldisc.2015.22
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发表时间：
2015
期刊：
影响因子：
33.5
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Luo Y;Zhu D;Du R;Gong Y;Xie C;Xu X;Fan Y;Yu B;Sun X;Chen Y
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、可靠的基因匹配多能细胞来源。最近，有研究发现，在细胞重编程为iPSCs的过程中，具有13或17环染色体的细胞通过代偿性单代二体性自主纠正缺陷。这一突破性发现提示了修复大规模染色体畸变的潜在治疗方法。然而，由于环染色体样本的稀缺性，这种方法在不同个体中的可重复性尚未得到仔细评估。此外，潜在的机制和适用于其他类型的染色体畸变仍然未知。在这里，我们从4个45，x绒毛膜绒毛成纤维细胞系中生成了iPSCs，发现只有一个重编程细胞系通过整个X染色体的双亲二体化获得了46，xx核型。通过逆转录病毒或表观重编程，核型校正在同一细胞系中是可重复的。经核型校正的iPSCs经X染色体失活处理后，其集落形态优于其他未校正的iPSCs，增殖率较高。进一步的转录组学比较在成纤维细胞系中发现了细胞周期调节因子在不校正细胞系中的独特表达模式。这些发现表明，iPSC技术具有纠正X单体的潜力，但纠正率非常低，可能是由于个体之间细胞周期基因的调节差异。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。
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.