c-Myc Is Dispensable for Direct Reprogramming of Mouse Fibroblasts

Cell stem cell (Impact Factor: 22.27). 02/2008; 2(1):10-2. DOI: 10.1016/j.stem.2007.12.001
Source: PubMed


Retroviral transduction of the four transcription factors Oct4, Sox2, Klf4, and c-Myc has been shown to initiate a reprogramming process that results in the transformation of mouse fibroblasts into embryonic stem (ES)-like cells designated as induced pluripotent stem (iPS) cells (Maherali et al., 2007, Meissner et al., 2007, Okita et al., 2007, Takahashi and Yamanaka, 2006 and Wernig et al., 2007). The promise of somatic reprogramming is the possibility to generate pluripotent stem cells that are patient specific and can be used as a unique source for autologous cell types for transplantation therapy (Jaenisch, 2004 and Yamanaka, 2007). Many iPS cell-derived animals develop tumors due to the reactivation of the c-Myc virus (Okita et al., 2007), and this represents a major safety concern if we want to translate this approach to humans. It is thus of great importance to achieve reprogramming without this particular oncogene in the future. Here we show that fibroblasts can be reprogrammed to a pluripotent state by Oct4, Sox2, and Klf4 in the absence of c-Myc.

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    • "During reprogramming, Oct4, Sox2 and Klf4 act as the core pluripotency network which is generally believed to be crucial for specifying cell fate change, whereas simply assists OSK to access target sites for amplifying transcriptional outputs [81]. Indeed, few differences are present between the two types of iPSCs (OSKM-induced and OSK-induced) in terms of analyses of phenotype, molecular biology, cytochemistry and non-programmed differentiation [80] [82] [83]. However, marked differences were evident when the two types of iPSCs were examined for germline contribution. "
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    ABSTRACT: The process of germline development carries genetic information and preparatory totipotency across generations. The last decade witnessed remarkable successes in the generation of germline cells from mouse pluripotent stem cells, especially induced germline cells with the capacity for producing viable offspring, suggesting clinical applications of induced germline cells in humans. However, to date, the culture systems for germline induction with accurate sex-specific meiosis and epigenetic reprogramming have not been well-established. In this study, we primarily focus on the mouse model to discuss key signaling events for germline induction. We review mechanisms of competent regulators on primordial germ cell induction and discuss current achievements and difficulties in inducing sex-specific germline development. Furthermore, we review the developmental identities of mouse embryonic stem cells and epiblast stem cells under certain defined culture conditions as it relates to the differentiation process to become germline cells.
    Preview · Article · Dec 2015 · Biology of Reproduction
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    • "Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) share some similarities to cancer cells, including the capacity to bypass senescence and form tumors upon transplantation (Goding et al., 2014). Accordingly, some genes often associated with cancer, such as Myc (Nakagawa et al., 2008; Wernig et al., 2008), p53 (Krizhanovsky and Lowe, 2009), and telomerase (Batista et al., 2011; Park et al., 2008), have been implicated in cellular reprogramming. Additionally, two reprogramming factors, Oct4 and Sox2, can be oncogenic in some cellular contexts (Hochedlinger et al., 2005; Lu et al., 2010; Rudin et al., 2012; Sarkar and Hochedlinger, 2013). "
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    ABSTRACT: Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.
    Full-text · Article · Jan 2015 · Cell Stem Cell
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    • "Six common nuclear reprogramming factors (OCT4, SOX2, KLF4, C-MYC, NANOG, and LIN28) are extensively used for generating iPS cells. However, it is possible to reprogram somatic cells with three transcription factors OCT4, SOX2 and KLF4, excluding c-MYC15 as it is naturally oncogenic (7,8). Although, the efficiency is reported to be low (7). "
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    ABSTRACT: Research related to induce pluripotent stem (iPS) cell generation has increased rapidly in recent years. Six transcription factors, namely OCT4, SOX2, C-MYC, KLF4, NANOG, and LIN28 have been widely used for iPS cell generation. As there is a lack of data on intra- and inter-networking among these six different transcription factors, the objective of this study is to analyze the intra- and inter-networks between them using bioinformatics. In this computational biology study, we used AminoNet, MATLAB to examine networking between the six different transcription factors. The directed network was constructed using MATLAB programming and the distance between nodes was estimated using a phylogram. The protein-protein interactions between the nuclear reprogramming factors was performed using the software STRING. The relationship between C-MYC and NANOG was depicted using a phylogenetic tree and the sequence analysis showed OCT4, C-MYC, NANOG, and SOX2 together share a common evolutionary origin. This study has shown an innovative rapid method for the analysis of intra and inter-networking among nuclear reprogramming factors. Data presented may aid researchers to understand the complex regulatory networks involving iPS cell generation.
    Full-text · Article · Dec 2014 · Cell Journal
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