Acquired genetic changes in human pluripotent stem cells: origins and consequences

Abstract

In the twenty years since human embryonic stem cells, and subsequently induced pluripotent stem cells (collectively, pluripotent stem cells), were first described, it has become apparent that these cells may acquire genetic changes during long term culture, commonly manifest by gains or losses of particular chromosomal regions, or by mutations in certain cancer associated genes, especially TP53. Such changes raise concerns for the safety of products destined for clinical applications in regenerative medicine. Although acquired changes may not be present in a cell line at the start of a research program, the low sensitivity of current detection methods means that mutations may be difficult to detect if they arise but are only present in a small proportion of the cells. Nevertheless, recent work suggests that the underlying mutation rate in pluripotent stem cells is low, though 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, pluripotent stem cells are programmed to die in response to genomic damage, which may reflect the requirements of early embryogenesis. Thus, the common variants that do occur are likely rare events that offer the cells a selective growth advantage.

Human Pluripotent Stem Cells: Genetic Instability or Stability?

“…In any event, one mechanism for the recurrent variants observed in PSCs is that they include mutations that tend to counter the normally low apoptotic threshold of these cells. Apart from BCL2L1 in the chr20 amplicon and TP53, candidate genes associated with gains of chromosomes 1q and 17q are anti-apoptotic while a candidate gene associated with the recurrent deletion on chromosome 18, NOXA, is pro-apoptotic and highly expressed in PSCs [3].…”

Understanding and Treating Niemann–Pick Type C Disease: Models Matter

“…As an example, acutely isolated cells combined with single cell transcriptomics [231] represent a first step that needs to be refined and extended with a focus on vulnerable cells in most affected organs, including the brain, liver, and lung. Cells differentiated from induced pluripotent stem cells represent an alternative although with caveats [397]. Whatever the source of cells, advanced culture systems preserving their three-dimensional arrangement should be considered as well [398,399].…”

von Willebrand disease: what does the future hold?

“…While a similar approach could also be applied using endothelial cells derived from induced pluripotent stem cells, human somatic cell therapy approaches are currently limited by the ability to generate sufficient amounts of cells to achieve physiological relevant expression levels after transplantation, the uncertain life-span of transplanted cells and the occurrence of genetic changes in the cells. 74 Progress on cellular therapies in other disease will certainly be helpful for the future development of this approach regarding VWD.…”