Progress in the Reprogramming of Somatic Cells

Gladstone Institute UCSF, The Gladstone Institute of Cardiovascular Disease, 1650 Owens St, San Francisco, CA 94158. .
Circulation Research (Impact Factor: 11.09). 02/2013; 112(3):562-574. DOI: 10.1161/CIRCRESAHA.111.249235
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: Direct reprogramming technology has emerged as an outstanding technique for the generation of induced pluripotent stem (iPS) cells and various specialized cells directly from somatic cells of different species. Recent studies dissecting the molecular mechanisms of reprogramming have methodologically improved the quality, ease and efficiency of reprogramming and eliminated the need for genome modifications with integrating viral vectors. With these advancements, direct reprogramming technology has moved closer to clinical application. Here, we provide a comprehensive overview of the cutting-edge findings regarding distinct barriers of reprogramming to pluripotency, strategies to enhance reprogramming efficiency, and chemical reprogramming as one of the non-integrating approaches in iPS cell generation. In addition to direct transdifferentiation, pluripotency factor-induced transdifferentiation or cell activation and signaling directed (CASD) lineage conversion is described as a robust strategy for the generation of both tissue-specific progenitors and clinically relevant cell types. Then, we consider the possibility that a combined method of inhibition of roadblocks (e.g. p53, p21, p57, Mbd3, etc.), and application of enhancing factors in a chemical reprogramming paradigm would be a safe, reliable and effective approach in pluripotent reprogramming and transdifferentiation. Furthermore, with respect to the state of native, aberrant, and target gene regulatory networks in reprogrammed cell populations, CellNet is reviewed as a computational platform capable of evaluating the fidelity of reprogramming methods and refining current engineering strategies. Ultimately, we conclude that a faithful, highly efficient and integration-free reprogramming paradigm would provide powerful tools for research studies, drug-based induced regeneration, cell transplantation therapies and other regenerative medicine purposes.
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