NUCLEAR REPROGRAMMING AND THE CURRENT CHALLENGES IN ADVANCING PERSONALIZED PLURIPOTENT STEM CELL-BASED THERAPIES

Abstract

John Gurdon's discovery that somatic cells could be reprogrammed back into a pluripotent state has immense implications across multiple different fields, including the future potential for autologous cellular therapies. This review briefly examines the history of nuclear reprogramming, from Gurdon's original work in amphibia, through the generation of oocyte-reprogrammed pluripotent stem cells in the non-human primate and recent defined factor-based reprogramming approaches to generate human induced pluripotent stem (iPS) cells. This review also examines the five principle challenges towards safely advancing pluripotent stem cell derivatives into personalized human therapeutics, specifically: genetic stability, epigenetic memory, post-transplantation efficacy, post-transplantation safety and feasibility, and additionally discusses various hypotheses that may play a role in resolving the aforementioned challenges. Focused on iPS cells and derivatives, these hypotheses essentially deal with aging research, genomic stability and culture conditions, immunogenicity and epigenetic memory, epigenetic memory elimination by chromatin modifying chemicals or by developmental competence factors and/or by candidate oocyte reprogramming factors (CORFs), and small molecules acting on the blood-brain-barrier. In light of these hypotheses, progress in nuclear reprogramming mechanistic are discussed in terms of securing the therapeutic promise of autologous reprogrammed personalized stem cell derivatives in the foreseeable future, thereby opening a probable new era for anti-aging control and regenerative medicine.