Two supporting factors greatly improve the efficiency of human iPSC generation.

Cell stem cell (Impact Factor: 23.56). 12/2008; 3(5):475-9. DOI: 10.1016/j.stem.2008.10.002
Source: PubMed

ABSTRACT Human fibroblasts can be induced into pluripotent stem cells (iPSCs), but the reprogramming efficiency is quite low. Here, we screened a panel of candidate factors in the presence of OCT4, SOX2, KLF4, and c-MYC in an effort to improve the reprogramming efficiency from human adult fibroblasts. We found that p53 siRNA and UTF1 enhanced the efficiency of iPSC generation up to 100-fold, even when the oncogene c-MYC was removed from the combinations.

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    ABSTRACT: Because of their pluripotent characteristics, human induced pluripotent stem cells (iPSCs) possess great potential for therapeutic application and for the study of degenerative disorders. These cells are generated from normal somatic cells, multipotent stem cells, or cancer cells. They express embryonic stem cell markers, such as OCT4, SOX2, NANOG, SSEA-3, SSEA-4, and REX1, and can differentiate into all adult tissue types, both in vitro and in vivo. However, some of the pluripotency-promoting factors have been implicated in tumorigenesis. Here, we describe the merits of tumor suppresser genes as reprogramming factors for the generation of iPSCs without tumorigenic activity. The initial step of reprogramming is induction of the exogenous pluripotent factors to generate the oxidative stress that leads to senescence by DNA damage and metabolic stresses, thus inducing the expression of tumor suppressor genes such as p21CIP1 and p16INK4a through the activation of p53 to be the pre-induced pluripotent stem cells (pre-iPSCs). The later stage includes overcoming the barrier of reprogramming-induced senescence or cell-cycle arrest by shutting off the function of these tumor suppressor genes, followed by the induction of endogenous stemness genes for the full commitment of iPSCs (full-iPSCs). Thus, the reactive oxygen species (ROS) produced by oxidative stress might be critical for the induction of endogenous reprogramming-factor genes via epigenetic changes or antioxidant reactions. We also discuss the critical role of tumor suppressor genes in the evaluation of the tumorigenicity of human cancer cell-derived pluripotent stem cells, and describe how to overcome their tumorigenic properties for application in stem cell therapy in the field of regenerative medicine.
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