Molecular Obstacles to Clinical Translation of iPSCs

Abstract

The ability to reprogram somatic cells into induced pluripotent stem cells (iPSCs) using defined factors provides new tools for biomedical research. However, some iPSC clones display tumorigenic and immunogenic potential, thus raising concerns about their utility and safety in the clinical setting. Furthermore, variability in iPSC differentiation potential has also been described. Here we discuss whether these therapeutic obstacles are specific to transcription-factor-mediated reprogramming or inherent to every cellular reprogramming method. Finally, we address whether a better understanding of the mechanism underlying the reprogramming process might improve the fidelity of reprogramming and, therefore, the iPSC quality.

Transcriptome Profiling of Patient-Specific Human iPSC-Cardiomyocytes Predicts Individual Drug Safety and Efficacy Responses In Vitro

“…While the use of reprogramming technologies holds great promise for generation of such models, in some studies, divergent reprogramming or differentiation strategies, and chromosomal aberrations acquired during reprogramming and in vitro expansion, have been shown to cause phenotype variation in hiPSCs and their derivatives. (Martins-Taylor and Xu, 2012; Sgodda and Cantz, 2013; Tapia and Schöler, 2016). Such findings call into question the ability of differentiated hiPSC derivatives to reflect the genetic identity of the individual.…”

Patient-derived induced pluripotent stem cells in cancer research and precision oncology

“…Most of the remaining mutations were shown to have been acquired during expansion in culture or during differentiation, and at a rate similar to that of normal adult somatic cells that is consistent with estimates of spontaneous mutation acquisition during cell division 70–74 . It is therefore now clear that reprogramming per se is not mutagenic, and that iPSCs are not inherently genetically unstable 44,75 . However, these studies examined normal iPSCs and cannot exclude genomic instability as a feature of iPSCs from cancers.…”

Induced pluripotent stem cells, past and future

“…Fortunately, most of the initial concerns turned out to be based either on artifacts or on much more nuanced phenomena, rather than problems intrinsic to iPSCs (7). The idea of epigenetic memory arose from the finding that at an early stage of cell cultivation, iPSCs harbor DNA methylation remnants and exhibit differentiation propensities biased towards their cell of origin.…”