Progress in the Reprogramming of Somatic Cells
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: Derived from any somatic cell type and possessing unlimited self-renewal and differentiation potential, induced pluripotent stem cells (iPSCs) are poised to revolutionize stem cell biology and regenerative medicine research, bringing unprecedented opportunities for treating debilitating human diseases. To overcome the limitations associated with safety, efficiency, and scalability of traditional iPSC derivation, expansion, and differentiation protocols, biomaterials have recently been considered. Beyond addressing these limitations, the integration of biomaterials with existing iPSC culture platforms could offer additional opportunities to better probe the biology and control the behavior of iPSCs or their progeny in vitro and in vivo. Herein, we discuss the impact of biomaterials on the iPSC field, from derivation to tissue regeneration and modeling. Although still exploratory, we envision the emerging combination of biomaterials and iPSCs will be critical in the successful application of iPSCs and their progeny for research and clinical translation. © 2015 The Authors.The EMBO Journal 03/2015; 34(8). DOI:10.15252/embj.201490756 · 10.75 Impact Factor
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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. http://dx.doi.org/10.1101/019455
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose pathophysiology is poorly understood. Aiming to better understand the cause of motor neuron death, the use of experimental cell-based models increased significantly over the past years. In this scenario, much knowledge has been generated from the study of motor neurons derived from embryonic stem cells and induced pluripotent stem cells. These methods, however, have advantages and disadvantages, which must be balanced on experimental design. Preclinical studies provide valuable information, making it possible to combine diverse methods to build an expanded knowledge of ALS pathophysiology. In addition to using stem cells as experimental models for understanding disease mechanism, these cells had been quoted for therapy in ALS. Despite ethical issues involved in its use, cell therapy with neural stem cells stands out. A phase I clinical trial was recently completed and a phase II is on its way, attesting the method's safety. In another approach, mesenchymal stromal cells capable of releasing neuroregulatory and anti-inflammatory factors have also been listed as candidates for cell therapy for ALS, and have been admitted as safe in a phase I trial. Despite recent advances, application of stem cells as an actual therapy for ALS patients is still in debate. Here, we discuss how stem cells have been useful in modeling ALS and address critical topics concerning their therapeutic use, such as administration protocols, injection site, cell type to be administered, type of transplantation (autologous vs. allogeneic) among other issues with particular implications for ALS therapy. © 2015 International Society for Advancement of CytometryCytometry Part A 02/2015; 87(3). DOI:10.1002/cyto.a.22630 · 3.07 Impact Factor