Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Oct4 and Klf4 with Small-Molecule Compounds

Shi, Yan; Desponts, Caroline; Tae, Jeong; Hahm, Heung Sik; Schöler, Hans R.; Ding, Sheng

doi:10.1016/j.stem.2008.10.004

Cited by 828 publications

(624 citation statements)

References 21 publications

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“…cells and iPSCs may not be critical for the reprogramming process, as, by definition, these cells fail to become fully reprogrammed iPSCs. Recent identifications of small molecules capable of catalyzing or even replacing certain reprogramming factors provide an alternative means of analyzing the role of these four reprogramming factors in iPSC induction [22,[24][25][26][27]. Complicating this method, however, is the fact that small chemical compounds can bind to multiple targets and act on multiple signaling pathways that may not be relevant to the reprogramming process.…”

Section: Introductionmentioning

confidence: 99%

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

Lin

Perez

Lei³

et al. 2011

Stem Cells

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Induced pluripotent stem cells (iPSCs) can be reprogrammed from adult somatic cells by transduction with Oct4, Sox2, Klf4, and c-Myc, but the molecular cascades initiated by these factors remain poorly understood. Impeding their elucidation is the stochastic nature of the iPS induction process, which results in heterogeneous cell populations. Here we have synchronized the reprogramming process by a two-phase induction: an initial stable intermediate phase following transduction with Oct4, Klf4, and c-Myc, and a final iPS phase following overexpression of Sox2. This approach has enabled us to examine temporal gene expression profiles, permitting the identification of Sox2 downstream genes critical for induction. Furthermore, we have validated the feasibility of our new approach by using it to confirm that downregulation of transforming growth factor b signaling by Sox2 proves essential to the reprogramming process. Thus, we present a novel means for dissecting the details underlying the induction of iPSCs, an approach with significant utility in this arena and the potential for wide-ranging implications in the study of other reprogramming mechanisms. STEM

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Section: Introductionmentioning

confidence: 99%

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

Lin

Perez

Lei³

et al. 2011

Stem Cells

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“…These major drawbacks have severely impaired the utility of reprogrammed or deprogrammed or direct/trans-differentiated somatic cells as viable therapeutic approaches. Although small molecules used to induce hESC lineage-specific therapy derivatives are usually safe developmental signal molecules and morphogens, it should be cautious of the small molecules used in the reverse process to generate iPS cells or trans-differentiation, which are known toxic cancerogenic chemicals with too dangerous or even lethal side effects to be used for patients [3,21,48,49,63]. …”

Section: Defined Platform For Well-controlled Derivation Maintenamentioning

confidence: 99%

Constraining the Pluripotent Fate of Human Embryonic Stem Cells for Tissue Engineering and Cell Therapy – The Turning Point of Cell-Based Regenerative Medicine

Parsons¹

2013

BBJ

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To date, the lack of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing safe and effective cell-based therapies for regenerating the damaged or lost CNS structure and circuitry in a wide range of neurological disorders. Similarly, the lack of a clinically-suitable human cardiomyocyte source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart. Given the limited capacity of the CNS and heart for self-repair, there is a large unmet healthcare need to develop stem cell therapies to provide optimal regeneration and reconstruction treatment options to restore normal tissues and function. Derivation of human embryonic stem cells (hESCs) provides a powerful in vitro model system to investigate molecular controls in human embryogenesis as well as an unlimited source to generate the diversity of human somatic cell types for regenerative medicine. However, realizing the developmental and therapeutic potential of hESC derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation. Recent advances and breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. Retinoic acid was identified as sufficient to induce the specification of neuroectoderm direct from the pluripotent state of hESCs and trigger a cascade of neuronal lineage-specific progression to human neuronal progenitors and neurons of the developing CNS in high efficiency, purity, and neuronal lineage specificity by promoting nuclear translocation of the neuronal specific transcription factor Nurr-1. Similarly, nicotinamide was rendered sufficient to induce the specification of cardiomesoderm direct from the pluripotent state of hESCs by promoting the expression of the earliest cardiac-specific transcription factor Csx/Nkx2.5 and triggering progression to cardiac precursors and beating cardiomyocytes with high efficiency. This technology breakthrough enables direct conversion of pluripotent hESCs into a large supply of high purity neuronal cells or heart muscle cells with adequate capacity to regenerate CNS neurons and contractile heart muscles for developing safe and effective stem cell therapies. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. Such milestone advances and medical innovations in hESC research allow generation of a large supply of clinical-grade hESC therapy derivatives targeting for major health problems, bringing cell-ba...

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“…Although iPSCs have a distinct morphology and express molecular markers similar to ESCs, their capacity for multilineage differentiation after embryo complementation is extremely varied (Wernig et al, 2007;Shi et al, 2008a;Feng et al, 2009a). During reprogramming to pluripotency, there were the events of copy number variation, mutations of protein-coding regions, karotypic abnormalities and aberrant slicing of imprinting genes in iPS cells (Stadtfeld et al, 2010;Gore et al, 2011;Hussein et al, 2011).…”

Section: Improving the Quality Of Ips Cellsmentioning

confidence: 99%

Overcoming barriers to the clinical utilization of iPSCs: reprogramming efficiency, safety and quality

et al. 2012

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Differentiated cells can be reprogrammed into pluripotent stem cells, known as "induced pluripotent stem cells" (iPSCs), through the overexpression of defined transcription factors. The creation of iPSC lines has opened new avenues for patient-specific cell replacement therapies for regenerative medicine. However, the clinical utilization of iPSCs is largely impeded by two limitations. The first limitation is the low efficiency of iPSCs generation from differentiated cells. The second limitation is that many iPSC lines are not authentically pluripotent, as many cell lines inefficiently differentiate into differentiated cell types when they are tested for their ability to complement embryonic development. Thus, the "quality" of iPSCs must be increased if they are to be differentiated into specialized cell types for cell replacement therapies. Overcoming these two limitations is paramount to facilitate the widespread employment of iPSCs for therapeutic purposes. Here, we summarize recent progress made in strategies enabling the efficient production of high-quality iPSCs, including choice of reprogramming factors, choice of target cell type, and strategies to improve iPSC quality.

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Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Oct4 and Klf4 with Small-Molecule Compounds

Cited by 828 publications

References 21 publications

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

Constraining the Pluripotent Fate of Human Embryonic Stem Cells for Tissue Engineering and Cell Therapy – The Turning Point of Cell-Based Regenerative Medicine

Overcoming barriers to the clinical utilization of iPSCs: reprogramming efficiency, safety and quality

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