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, especially TP53. 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.

自人类胚胎干细胞和随后的诱导多能干细胞首次被描述以来的 20 年里，很明显，在长期培养过程中，这些细胞（统称为“多能干细胞”（PSC））可以获得遗传基因变化，通常包括特定染色体区域的获得或损失，或某些癌症相关基因的突变，尤其是TP53. 这些变化引发了人们对用于再生医学的 PSC 衍生细胞疗法的安全性的担忧。尽管在研究计划开始时细胞系中可能不存在获得性遗传变化，但当前检测方法的低灵敏度意味着突变可能难以检测到它们是否出现，但仅存在于一小部分细胞中。在这篇综述中，我们讨论了人类 PSC 获得的突变类型以及导致它们积累的机制。最近的研究表明，PSC 的潜在突变率很低，尽管它们似乎也特别容易受到基因组损伤的影响。这种明显的矛盾可以通过以下观察来调和，即与体细胞相比，PSC 被编程为响应基因组损伤而死亡，这可能反映了早期胚胎发生的要求。因此，观察到的常见遗传变异可能是赋予细胞选择性生长优势的罕见事件。