Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts

Nakagawa, Masato; Koyanagi, Michiyo; Tanabe, Koji; Takahashi, Kazutoshi; Ichisaka, Tomoko; Aoi, Takashi; Okita, Keisuke; Mochiduki, Yuji; Takizawa, Nanako; Yamanaka, Shinya

doi:10.1038/nbt1374

Cited by 2,551 publications

(2,011 citation statements)

References 18 publications

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“…Despite significant attention from many researchers, the exact mechanisms by which Yamanaka factors lead to iPSC induction have remained difficult to dissect [20,43,44]. Among the four factors, c-Myc is not necessary for the reprogramming of somatic cells into iPSCs [45,46]. Furthermore, recent studies have shown that both mouse and human neural stem cells can be reprogrammed to iPSCs with Oct4 and Klf4, or Oct4 alone [47][48][49].…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…38)-40) The iPS cells were also established using three factors without c-MYC, which harbors the highest risk of oncogenesis among these OSKM factors. 41) Some iPS cells even passed the most stringent test for pluripotency; tetraploid complementation. 42)- 46) The cells of tetraploid embryos can contribute to extraembryonic tissues, but not to embryonic tissues.…”

Section: Induction Of Pluripotency By Defined Factorsmentioning

confidence: 99%

Induction of pluripotency by defined factors

Okita

Yamanaka

2010

Experimental Cell Research

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Abstract:The "reversion of cell fate from differentiated states back into totipotent or pluripotent states" has been an interest of many scientists for a long time. With the help of knowledge accumulated by those scientists, we succeeded in converting somatic cells to a pluripotent cell lineage by the forced expression of defined factors. These established induced pluripotent stem (iPS) cells have similar features to embryonic stem (ES) cells, including pluripotency and immortality. The iPS cell technology provides unprecedented opportunities for regenerative medicine and drug discovery.

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“…Oct4 is considered to be a unique reprogramming factor, as it could not be replaced by other paralogous members of the POU (Pit‐Unc‐POU) protein family, while both Sox2 and Klf4 are replaceable and c‐Myc can be omitted altogether 2. Exogenous Oct4 is the most common component of reprogramming mixtures, and activation of endogenous Oct4 is a crucial step in inducing pluripotency.…”

Section: Introductionmentioning

confidence: 99%

Changing POU dimerization preferences converts Oct6 into a pluripotency inducer

Jerabek

et al. 2016

EMBO Reports

123

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The transcription factor Oct4 is a core component of molecular cocktails inducing pluripotent stem cells (iPSCs), while other members of the POU family cannot replace Oct4 with comparable efficiency. Rather, group III POU factors such as Oct6 induce neural lineages. Here, we sought to identify molecular features determining the differential DNA‐binding and reprogramming activity of Oct4 and Oct6. In enhancers of pluripotency genes, Oct4 cooperates with Sox2 on heterodimeric SoxOct elements. By re‐analyzing ChIP‐Seq data and performing dimerization assays, we found that Oct6 homodimerizes on palindromic OctOct more cooperatively and more stably than Oct4. Using structural and biochemical analyses, we identified a single amino acid directing binding to the respective DNA elements. A change in this amino acid decreases the ability of Oct4 to generate iPSCs, while the reverse mutation in Oct6 does not augment its reprogramming activity. Yet, with two additional amino acid exchanges, Oct6 acquires the ability to generate iPSCs and maintain pluripotency. Together, we demonstrate that cell type‐specific POU factor function is determined by select residues that affect DNA‐dependent dimerization.

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Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts

Cited by 2,551 publications

References 18 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

Induction of pluripotency by defined factors

Changing POU dimerization preferences converts Oct6 into a pluripotency inducer

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