( C) Changes in the DNA sequence commonly observed in iPSCs, including single nucleotide variation, ie, substitution of a single nucleotide at a specific position in the genome by another single nucleotide, and loss (deletion) or gain (insertion) of a single nucleotide. ( B) Chromosomal rearrangements commonly observed in iPSCs, including gain of whole chromosomes, translocation of a chromosomal part from one to another chromosome, deletion of a chromosomal part, and duplications of a chromosomal part. ( A) Genetic alterations in iPSCs mainly arise via 3 routes: (i) Mutations are already present in the parental somatic cells from which iPSCs are derived and are subsequent cultured and expanded (upper panel), (ii) mutations can be induced during the process of reprogramming (middle panel), and (iii) mutations can be induced during extended passaging and prolonged culturing (lower panel). Sources and consequences of genomic instability in iPSCs. Furthermore, epigenetic memory of the somatic cells in iPSCs may influence lineage-specific differentiation and with-it utility and safety for clinical use. Therefore, to warrant safety of iPSCs for clinical applications, analysis of genetic integrity should be carried out on a regular basis. Genetic aberrations could be acquired during the process of reprogramming or due to extended passaging of iPSCs, which likewise limit their utility and safety. ( B) Pre-existing genetic abnormalities of somatic cells can, when remaining undiscovered in the generated iPSCs, seriously limit their utility and safety for clinical or regenerative therapy. Overall, the generated iPSCs can be differentiated into specialized cells and used as a tool for disease modeling, personalized medicine, regenerative therapy, and tissue engineering, in addition to their use for drug screening or drug testing. Alternatively, non-integrative strategies for reprogramming yield iPSCs, which are free of transgenes and are considered safe. Reprogramming of somatic cells by integrative strategies yields iPSCs with the integrations of transgenes into the genome, which may possess an increased mutagenic potential and are therefore considered unsafe. ( A) Generation of iPSCs from a variety of somatic cell types by using integrative or non-integrative reprogramming approaches. Process toward reprogramming of somatic cells to generate patient-specific iPSCs and application fields of iPSC-derived specialized cells. The present review discusses the somatic cell origin, genetic stability, and epigenetic memory of iPSCs and their impact on basic and translational research.Įpigenetic memory genetic aberrations genetic stability human induced pluripotent stem cells point mutations somatic origin. However, residual epigenetic memory influences the iPSC phenotype, which may affect their application in disease therapeutics. Changes in chromatin structure by DNA methylations and histone tail modifications aim to reset the gene expression pattern of somatic cells to facilitate and establish self-renewal and pluripotency. On the other hand, reprogramming of somatic cells to iPSCs requires profound modifications in the epigenetic landscape. Therefore, to warrant the safety of human iPSCs for clinical applications, analysis of genetic integrity, particularly during iPSC generation and differentiation, should be carried out on a regular basis. Genetic aberrations could be present in donor somatic cells and then transferred during iPSC generation, or they could occur as de novo mutations during reprogramming or prolonged cell culture. As the genome of iPSCs thoroughly reproduces that of the somatic cells from which they are derived, they may possess genetic abnormalities, which would seriously compromise their utility and safety. The potential of human induced pluripotent stem cells (iPSCs) to self-renew indefinitely and to differentiate virtually into any cell type in unlimited quantities makes them attractive for in vitro disease modeling, drug screening, personalized medicine, and regenerative therapies.
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