Abstract
Evaluation of the extent and nature of induced pluripotent stem cell (iPSC) genetic instability is important for both basic research and future clinical use. As previously demonstrated regarding embryonic stem cells, such DNA aberrations might affect the differentiation capacity of the cells and increase their tumorigenicity. Here, we first focus on the contribution of multiple DNA damage response pathways during cellular reprogramming. We then discuss the origin and mechanisms responsible for the modification of genetic material in iPSCs (pre-existing variations in somatic cells, mutations induced by reprogramming factors, and mutations induced by culture expansion) and deepen the possible functional consequences of genetic variations in these cells. Lastly, we present some recent improvements of iPSC generation methods aimed at obtaining cells with fewer genetic variations.
Highlights
Induced pluripotent stem cells hold equivalent embryonic stem cells (ESC) properties [1,2,3] and are great promise for clinical applications because of their potential use in personalized cell therapy or disease modeling [4]
We discuss the origin and mechanisms responsible for the modification of genetic material in induced pluripotent stem cell (iPSC) and deepen the possible functional consequences of genetic variations in these cells
As the above studies had focused on fibroblast-derived human iPSCs (hiPSCs), in order to assess if alternative cell sources would guarantee increased genetic stability based on their different reprogramming efficiencies, Ruiz et al characterized the genomic integrity of eight hiPSC lines derived from five different non-fibroblast somatic cell types [45]
Summary
Induced pluripotent stem cells (iPSCs) hold equivalent embryonic stem cells (ESC) properties (self renewal and ability to differentiate into all three embryonic germ layers) [1,2,3] and are great promise for clinical applications because of their potential use in personalized cell therapy or disease modeling [4]. Gonzalez et al [18] showed that ectopic expression of the reprogramming factors was sufficient to induce DNA DSBs in mouse iPSCs cells They showed that efficient reprogramming required key HR genes, including Brca, Brca and Rad51 [18]. Other evidence of the importance of DDR pathways is the observation that deficiency of Ataxia-telangiectasia mutated (ATM), a protein kinase that has a critical role in the response to DNA double strand breaks [23], decreases reprogramming efficiency and increases genomic instability in mouse iPSCs [24]. Since DDR pathways have been shown to be widely involved in the reprogramming process, it is not surprising to note that their defects are linked to genetic instability in iPSCs, owing to inefficient DNA repair and/or the preferential use of error-prone mechanisms. These observations highlight that iPS reprogramming involves DDR machinery activation and that an efficient repair mechanism is needed to allow successful cell reprogramming
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
