Concise Review: Deciphering the Mechanism Behind Induced Pluripotent Stem Cell Generation

Regenerative medicine using pluripotent/multipotent stem cells holds a great promise in developing therapies for treating developmental abnormalities, degenerative disorders, and aging-related illness. However, supply and safety of the stem cells are two major problems with today's regenerative medicine. Recent development of induced pluripotent stem cells (iPSCs) has overcome the supply shortages by allowing the reprogramming of patients' body cells to embryonic stem cell (ESC)-like pluripotent cells. Still, the potential tumorigenicity of iPSCs remains as an obstacle. During early embryogenesis ESCs can be generated without tumor formation; therefore, understanding the mechanisms underlying ESC generation may help us to prevent iPSC tumorigenicity. Previous studies have shown that an ESC-enriched noncoding RNA, miR-302, induces somatic cell reprogramming (SCR) to form iPSCs, suggesting its pivotal role in stem cell generation. Recent research further revealed that miR-302-induced SCR involves an epigenetic reprogramming mechanism similar to the natural zygotic reprogramming process in the two-to eight-cell-stage embryos. These findings indicate that miR-302, as a cytoplasmic gene silencer, inhibits the translation of multiple key epigenetic regulators, including AOF1/2, methyl-CpG binding proteins 1 and 2, and DNA (cytosine-5-)-methyltransferase 1, to induce global DNA demethylation, which subsequently triggers the activation of the previously defined factors Oct4, Sox2, and Nanog to complete the reprogramming process. The same mechanism was also found in the event of somatic cell nuclear transfer. Based on these advanced understandings, this review describes the currently established SCR mechanism-as compared to the natural process of early ESC formation-and demonstrates how stem cell researchers may use this mechanism to improve iPSC generation. STEM CELLS 2011;29:1645-1649