Inducing iPSCs to escape the dish

Abstract

Induced pluripotent stem cells (iPSCs) hold great promise for autologous cell therapies, but significant roadblocks remain to translating iPSCs to the bedside. For example, concerns about the presumed autologous transplantation potential of iPSCs have been raised by a recent paper demonstrating that iPSC-derived teratomas were rejected by syngeneic hosts. Additionally, the reprogramming process can alter genomic and epigenomic states, so a key goal at this point is to determine the clinical relevance of these changes and minimize those that prove to be deleterious. Finally, thus far few studies have examined the efficacy and tumorigenicity of iPSCs in clinically relevant transplantation scenarios, an essential requirement for the FDA. We discuss potential solutions to these hurdles to provide a roadmap for iPSCs to "jump the dish" and become useful therapies.

Figure 1. Genetic and Epigenetic Alterations Observed in hiPSCs

Reprogramming can cause cells to have an abnormal karyotype (particularly gains of chromosome 12 and 17), copy number variation, and point mutations, all tending toward amplification/overexpression of oncogenes and deletion/inactivation of tumor suppressors. At the epigenetic level, reprogrammed cells can retain a memory of the starting tissue from which they were derived. The cells can exhibit DNA methylation defects, particularly at CpG island shores, and aberrant histone modifications. They can also vary in X chromosome inactivation status.