Reprogramming mature differentiated cells to a pluripotent state can be achieved by the ectopic expression of four transcription factors: Oct4, Klf4, Sox2 and cMyc (OKSM). This method of generating induced pluripotent stem cells (iPSCs) is a potentially powerful tool to produce patient-specific stem cells for therapy and to dissect the biology of cell fate specification. Furthermore, similar to cancer cells, iPSCs have limitless replication potential, and the inactivation of major tumour suppressors p53 and retinoblastoma protein are known to enhance the efficiency of reprogramming. This suggests that insights into reprogramming will also carry implications for our understanding of cancer biology.
Among many approaches to study reprogramming, examination of factors that promote or impede the process has provided much insight into its mechanism. Since studies by others have demonstrated that cell death is an obstacle to efficient iPSC generation, the role of individual cell death mediators in reprogramming was investigated. Apoptosis and necroptosis are distinct programmed cell death pathways that are driven by the interaction between defined molecular mediators. Using murine cell models and chemical inhibitors, the influence of apoptosis mediators Bax, Bak and caspases, as well as the necroptosis mediator RIP3 over iPSC generation was examined. The reprogramming efficiency in conditions of varying cell death capacity was measured using established pluripotency markers such as Nanog, and preliminary studies were undertaken to assess the pluripotency of resultant iPSCs. The findings of this study will help elucidate the relationship between cell death and reprogramming, and are expected to aid strategies to manipulate cell fate and enhance the reprogramming process for clinical applications.