In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state

Wernig, Marius; Meissner, Alexander; Foreman, Ruth K.; Brambrink, Tobias; Ku, Manching; Hochedlinger, Konrad; Bernstein, B; Jaenisch, Rudolf

doi:10.1038/nature05944

Cited by 2,474 publications

(1,930 citation statements)

References 33 publications

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“…Some also consider this approach illogical given the paucity of human oocytes and the concerns of viral transmission if animal oocytes are used. Recently, fetal and adult somatic cells were successfully reprogrammed to the pluripotent state using transfection of four pluripotent genes (OCT4, SOX2, NANOG, LIN28, KLF4, cMYC) (induced pluripotent stem cells, iPSCs) [Takahashi et al, 2007;Wernig et al, 2007]. This is a major breakthrough in stem cell biology and alleviates the immunorejection and ethical issues, but it is also fraught with hurdles that need to be overcome such as ''partial reprogramming'' possibly leading to unstable epigenesis, the implications of the viral vector and the production of teratomas.…”

Section: Immunorejectionmentioning

confidence: 99%

Taking stem cells to the clinic: Major challenges

Bongso

Fong

Gauthaman

2008

J of Cellular Biochemistry

165

111

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Stem cell therapy offers tremendous promise in the treatment of many incurable diseases. A variety of stem cell types are being studied but human embryonic stem cells (hESCs) appear to be the most versatile as they are pluripotent and can theoretically differentiate into all the tissues of the human body via the three primordial germ layers and the male and female germ lines. Currently, hESCs have been successfully converted in vitro into functional insulin secreting islets, cardiomyocytes, and neuronal cells and transfer of such cells into diabetic, ischaemic, and parkinsonian animal models respectively have shown successful engraftment. However, hESC-derived tissue application in the human is fraught with the problems of ethics, immunorejection, tumorigenesis from rogue undifferentiated hESCs, and inadequate cell numbers because of long population doubling times in hESCs. Human mesenchymal stem cells (hMSC) though not tumorigenic, also have their limitations of multipotency, immunorejection, and are currently confined to autologous transplantation with the genuine benefits in allogeneic settings not conclusively shown in large controlled human trials. Human Wharton's jelly stem cells (WJSC) from the umbilical cord matrix which are of epiblast origin and containing both hESC and hMSC markers appear to be less troublesome in not being an ethically controversial source, widely multipotent, not tumorigenic, maintain ''stemness'' for several serial passages and because of short population doubling time can be scaled up in large numbers. This report describes in detail the hurdles all these stem cell types have to overcome before stem cell-based therapy becomes a genuine reality.

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Section: Immunorejectionmentioning

confidence: 99%

Taking stem cells to the clinic: Major challenges

Bongso

Fong

Gauthaman

2008

J of Cellular Biochemistry

165

111

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“…Pioneering work by Yamanaka and colleagues (2006) identified the first set of these dominant factors: Oct4, Sox2, Klf4, and c-Myc (OSKM). Induced pluripotent stem cells (iPSCs) obtained by transduction of these Yamanaka factors or other combinations are epigenetically and developmentally very similar, if not identical, to ESCs [8][9][10][11][12]. Although the identification of factors able to induce this reprogramming represents a major advancement, much work remains to elucidate the exact molecular mechanism underlying this direct cell reprogramming [13].…”

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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“…It was recently revealed that ES cell-like pluripotent stem cells, designated as induced pluripotent stem (iPS) cells, can be generated by the simultaneous introduction of several genes for reprogramming factors, such as Oct3/4, Sox2, Klf4, and c-Myc, into somatic cells [13][14][15][16][17][18][19][20]. The issue of histoincompatibility between patients to be treated and ES cells may be overcome by the generation of iPS cells from somatic cells of the patients such as fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Dendritic Cells and Macrophages Generated by Directed Differentiation from Mouse Induced Pluripotent Stem Cells

et al. 2009

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Methods have been established to generate dendritic cells (DCs) from mouse and human embryonic stem (ES) cells. We designated them as ES-DCs and mouse models have demonstrated the induction of anti-cancer immunity and prevention of autoimmune disease by in vivo administration of genetically engineered ES-DCs. For the future clinical application of ES-DCs, the histoincompatibility between patients to be treated and available human ES cells and the ethical concerns associated with human ES cells may be serious obstacles. However, recently developed induced pluripotent stem (iPS) cell technology is expected to resolve these issues. This report describes the generation and characterization of DCs derived from mouse iPS cells. The iPS cell-derived DCs (iPS-DCs) possessed the characteristics of DCs including the capacity of T-cell-stimulation, antigen-processing and presentation and cytokine production. DNA microarray analyses revealed the upregulation of genes related to antigen-presenting functions during differentiation into iPS-DCs and similarity in gene expression profile in iPS-DCs and bone marrow cell-derived DCs. Genetically modified iPS-DCs expressing antigenic protein primed T-cells specific to the antigen in vivo and elicited efficient antigen-specific antitumor immunity. In addition, macrophages were generated from iPS cells (iPS-MP). iPS-MP were comparable with bone marrow cell-derived macrophages in the cell surface phenotype, functions, and gene expression profiles.

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In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state

Cited by 2,474 publications

References 33 publications

Taking stem cells to the clinic: Major challenges

Taking stem cells to the clinic: Major challenges

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

Characterization of Dendritic Cells and Macrophages Generated by Directed Differentiation from Mouse Induced Pluripotent Stem Cells

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