期刊
NATURE REVIEWS MOLECULAR CELL BIOLOGY
卷 21, 期 12, 页码 715-728出版社
NATURE PORTFOLIO
DOI: 10.1038/s41580-020-00292-z
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资金
- European Union's Horizon 2020 research and innovation programme [668724]
- UK Regenerative Medicine Platform, MRC [MR/R015724/1]
- MRC [MR/R015724/1] Funding Source: UKRI
Cultured pluripotent stem cells (PSCs) acquire genetic changes - gains or losses of entire chromosomal regions, or point mutations, including in cancer-associated genes such asTP53. Recent work provides insights into the mechanisms of mutation and selection, which have implications for the use of human PSCs in regenerative medicine. In the 20 years since human embryonic stem cells, and subsequently induced pluripotent stem cells, were first described, it has become apparent that during long-term culture these cells (collectively referred to as 'pluripotent stem cells' (PSCs)) can acquire genetic changes, which commonly include gains or losses of particular chromosomal regions, or mutations in certain cancer-associated genes, especiallyTP53. Such changes raise concerns for the safety of PSC-derived cellular therapies for regenerative medicine. Although acquired genetic changes may not be present in a cell line at the start of a research programme, the low sensitivity of current detection methods means that mutations may be difficult to detect if they arise but are present in only a small proportion of the cells. In this Review, we discuss the types of mutations acquired by human PSCs and the mechanisms that lead to their accumulation. Recent work suggests that the underlying mutation rate in PSCs is low, although they also seem to be particularly susceptible to genomic damage. This apparent contradiction can be reconciled by the observations that, in contrast to somatic cells, PSCs are programmed to die in response to genomic damage, which may reflect the requirements of early embryogenesis. Thus, the common genetic variants that are observed are probably rare events that give the cells with a selective growth advantage.
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