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.

中文翻译：

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体细胞重编程为多能干细胞过程中出现染色体畸变

将体细胞重编程为诱导性多能干细胞（iPSC）开辟了新的治疗可能性。但是，在iPSC中检测到的核型异常损害了其实用性，尤其是在早期传代中发现的染色体畸变引起了严重的安全隐患。早代iPSC中染色体异常的潜在机制尚不清楚。用KMOS（KLF4，cMYC，OCT4和SOX2）蛋白刺激人皮肤成纤维细胞（HDF），以增强其增殖能力，并获得了许多有力的克隆。通过KMOS mRNAs转染进行克隆重编程，以确认重编程过程的“染色体诱变性”。重建继代后，进行了传代培养以检查iPSC的核型稳定性。然后将抗氧化剂N-乙酰半胱氨酸（NAC）添加到培养基中，以进一步确认重编程前几天的诱变性。通过重新编程转录因子，在新诱导的iPS克隆的一小部分中发现了染色体畸变。克隆重编程排除了从罕见的核型异常父母细胞亚群继承的异常染色体。更重要的是，抗氧化剂NAC有效地减少了重新编程初期的染色体畸变。一旦建立了iPS细胞系，它们便在随后的亚培养中恢复了核型稳定性。我们的结果为重编程过程的“染色体诱变性”提供了第一线证据。通过重新编程转录因子，在新诱导的iPS克隆的一小部分中发现了染色体畸变。克隆重编程排除了从罕见的核型异常父母细胞亚群继承的异常染色体。更重要的是，抗氧化剂NAC有效地减少了重新编程初期的染色体畸变。一旦建立了iPS细胞系，它们便在随后的亚培养中恢复了核型稳定性。我们的结果为重编程过程的“染色体诱变性”提供了第一线证据。通过重新编程转录因子，在新诱导的iPS克隆的一小部分中发现了染色体畸变。克隆重编程排除了从罕见的核型异常父母细胞亚群继承的异常染色体。更重要的是，抗氧化剂NAC有效地减少了重新编程初期的染色体畸变。一旦建立了iPS细胞系，它们便在随后的亚培养中恢复了核型稳定性。我们的结果为重编程过程的“染色体诱变性”提供了第一线证据。抗氧化剂NAC在重新编程的早期有效地减少了染色体畸变的发生。一旦建立了iPS细胞系，它们便在随后的亚培养中恢复了核型稳定性。我们的结果为重编程过程的“染色体诱变性”提供了第一线证据。抗氧化剂NAC在重新编程的早期有效地减少了染色体畸变的发生。一旦建立了iPS细胞系，它们便在随后的亚培养中恢复了核型稳定性。我们的结果为重编程过程的“染色体诱变性”提供了第一线证据。