Chromosomal aberration arises during somatic reprogramming to pluripotent stem cells
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RESEARCH
Chromosomal aberration arises during somatic reprogramming to pluripotent stem cells Xinyu Liu1,2, Conghui Li1, Kang Zheng1, Xiaofeng Zhao1, Xiaofeng Xu1, Aifen Yang1, Min Yi1, Huaping Tao1, Binghua Xie1, Mengsheng Qiu1,2,3* and Junlin Yang1*
Abstract Background: 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. Methods: 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. Results: 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. Conclusions: Our results provided the first line of evidence for the ‘chromosomal mutagenicity’ of reprogramming process. Keywords: Induced pluripotent stem cell, Reprogramme, Karyotype, Chromosomal aberration, Genetic stability
*Correspondence: [email protected]; [email protected] 1 Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life and Environmental Sciences, Hangzhou Normal University, 311121 Hangzhou, China 3 Department of Anatomical Sciences and Neurobiology, University of Louisville, 40292 Louisville, KY, USA Full list of author information is available at the end of the article
Background Induced pluripotent stem cells (iPSCs) have become a valuable model system for studying tissue development and related human diseases, holding great promise for autogenous cell therapy [1].Further investigation focusing on the genetic stability of iPSCs is necessary, especially as genetic abnormalities in their therapeutic derivatives might harbor the risk of tumorigenesis [2]. Affirming a normal karyotype becomes a basic requirement when cultivating a iPS cell clone, since chromosomal
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