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Chromosomal aberration arises during somatic reprogramming to pluripotent stem cells

机译:在体细胞重新编程到多能干细胞期间产生染色体畸变

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Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) has opened new therapeutic possibilities. However, karyotypic abnormalities detected in iPSCs compromised their utility, especially chromosomal aberrations found at early passages raised serious safety concerns. The mechanism underlying the chromosomal abnormality in early-passage iPSCs is not known. Human dermal fibroblasts (HDFs) were stimulated with KMOS (KLF4, cMYC, OCT4 and SOX2) proteins to enhance their proliferative capacity and many vigorous clones were obtained. Clonal reprogramming was carried out by KMOS mRNAs transfection to confirm the ‘chromosomal mutagenicity’ of reprogramming process. Subculturing was performed to examine karyotypic stability of iPSCs after the re-establishment of stemness. And antioxidant N-acetyl-cysteine (NAC) was added to the culture medium for further confirmming the mutagenicity in the first few days of reprogramming. Chromosomal aberrations were found in a small percentage of newly induced iPS clones by reprogramming transcription factors. Clonal reprogramming ruled out the aberrant chromosomes inherited from rare karyotypically abnormal parental cell subpopulation. More importantly, the antioxidant NAC effectively reduced the occurrence of chromosomal aberrations at the early stage of reprogramming. Once iPS cell lines were established, they restored karyotypic stability in subsequent subculturing. Our results provided the first line of evidence for the ‘chromosomal mutagenicity’ of reprogramming process.
机译:对诱导多能干细胞(IPSC)进行重新编程的体细胞已开启新的治疗可能性。然而,在IPSCS中检测到的核型异常损害了它们的效用,特别是在早期通道中发现的染色体畸变提高了严重的安全问题。早期通道IPSCS中染色体异常的机制尚不清楚。用KMOS(KLF4,CMYC,OCT4和SOX2)蛋白刺激人的皮肤成纤维细胞(HDFS),以增强其增殖能力,并且获得许多剧烈的克隆。克隆重编程由kmosmRNA转染进行,以确认“重编程过程”的“染色体致突变性”。在重新建立茎后,进行了递推培养以检查IPSCs的核型稳定性。将抗氧化剂N-乙酰基半胱氨酸(NAC)加入到培养基中,以在重编程的前几天进一步证实致突变性。通过重编程转录因子,以小百分点的新诱导的IPS克隆发现染色体像差。克隆重编程排除了从罕见的核型异常父母细胞亚群中遗传的异常染色体。更重要的是,抗氧化NAc在重编程早期有效地降低了染色体畸变的发生。一旦建立了IPS细胞系,它们就会在随后的传代培养中恢复核型稳定性。我们的结果为重编程过程的“染色体致突变性”提供了第一线。

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