An insight into non-integrative gene delivery approaches to generate transgene-free induced pluripotent stem cells

Over a decade ago, a landmark study that reported derivation of induced Pluripotent Stem Cells (iPSCs) by reprogramming fibroblasts has transformed stem cell research attracting the interest of the scientific community worldwide. These cells circumvent the ethical and immunological concerns associated with embryonic stem cells, and the limited self-renewal ability and restricted differentiation potential linked to adult stem cells. iPSCs hold great potential for understanding basic human biology, in vitro disease modeling, high-throughput drug testing and discovery, and personalized regenerative medicine. The conventional reprogramming methods involving retro- and lenti-viral vectors to deliver reprogramming factors in somatic cells to generate iPSCs nullify the clinical applicability of these cells. Although these gene delivery systems are efficient and robust, they carry an enormous risk of permanent genetic modifications and are potentially tumorigenic. To evade these safety concerns and derive iPSCs for human therapy, tremendous technological advancements have resulted in the development of non-integrating viral- and non-viral approaches. These gene delivery techniques curtail or eliminate the risk of any genomic alteration and enhance the prospects of iPSCs from bench-to-bedside. The present review provides a comprehensive overview of non-integrating viral (adenoviral vectors, adeno-associated viral vectors, and Sendai virus vectors) and DNA-based, non-viral (plasmid transfection, minicircle vectors, transposon vectors, episomal vectors, and liposomal magnetofection) approaches that have the potential to generate transgene-free iPSCs. The understanding of these techniques could pave the way for the use of iPSCs for various biomedical applications.