Pluripotent stem cells can differentiate into nearly all types of cells in the body. This unique potential provides significant promise for cell-based therapies to restore tissues or organs destroyed by injuries, degenerative diseases, aging, or cancer. The discovery of induced pluripotent stem cell (iPSC) technology offers a possible strategy to generate patient-specific pluripotent stem cells. However, because of concerns about the specificity, efficiency, kinetics, and safety of iPSC reprogramming, improvements or fundamental changes in this process are required before their effective clinical use. A chemical approach is regarded as a promising strategy to improve and change the iPSC process. Dozens of small molecules have been identified that can functionally replace reprogramming factors and significantly improve iPSC reprogramming. In addition to the prospect of deriving patient-specific tissues and organs from iPSCs, another attractive strategy for regenerative medicine is transdifferentiation-the direct conversion of one somatic cell type to another. Recent studies revealed a new paradigm of transdifferentiation: using transcription factors used in iPSC generation to induce transdifferentiation or called iPSC transcription factor-based transdifferentiation. This type of transdifferentiation not only reveals and uses the developmentally plastic intermediates generated during iPSC reprogramming but also produces a wide range of cells, including expandable tissue-specific precursor cells. Here, we review recent progress of small molecule approaches in the generation of iPSCs. In addition, we summarize the new concept of iPSC transcription factor-based transdifferentiation and discuss its application in generating various lineage-specific cells, especially cardiovascular cells.
"The integrating approach typically employs viral vectors to deliver and integrate pluripotency genes. Unfortunately, this approach has the potential for insertional mutagenesis, or malignant transformation (Ma et al, 2013b). Hence, clinical translation of integrating methods is severely limited due to safety and efficiency concerns. "
"The loss of those factors in reprogrammed human amniotic membrane-derived iPSCs might benefit their potential therapeutic application. Upregulated CD44 expression may be a surrogate marker of p53 inactivation and associated plasticity; thus, we will screen for the risk of developing tumorigenicity using this CD44 marker . These approaches to avoid the cause of tumorigenicity might be useful when we treat stem cells or iPSCs with cancer-inducing agents, or when generating full reprogramming stem cells from somatic cells. "
[Show abstract][Hide abstract] 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.
Evgeniya A Vaskova, Sergey P Medvedev, Anastasiya E Sorokina, Artem A Nemudryy, Evgeniy A Elisaphenko, Irina S Zakharova, Alexander I Shevchenko, Elena A Kizilova, Antonina I Zhelezova, Ivan S Evshin, [...], Julia M Minina, Natalia S Zhdanova, Igor I Khegay, Fedor A Kolpakov, Gennadiy T Sukhikh, Evgeniy A Pokushalov, Alexander M Karaskov, Valentin V Vlasov, Ludmila N Ivanova, Suren M Zakian
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