Intracellular Signaling Pathways Regulating Pluripotency of Embryonic Stem Cells

Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Current Stem Cell Research & Therapy (Impact Factor: 2.21). 02/2006; 1(1):103-11. DOI: 10.2174/157488806775269061
Source: PubMed


The cytokine LIF and its downstream effector STAT3 are essential for maintenance of pluripotency in mouse ES cells. The requirement for the transcription factor Oct3/4 for ES cell pluripotency is also well-documented. However, LIF is not involved in self-renewal of human ES cells, suggesting that other pathways must play an important role in this process. The importance of other signal transduction pathways, including BMP and Wnt signalings, as well as novel transcription factors such as Nanog, is now being recognized. We will review the rapid progress that has been made in identifying and dissecting the intracellular signaling pathways that contribute to self-renewal of pluripotent mouse and human ES cells.

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    • "Pluripotency in mouse embryonic stem cells (mESCs) is controlled by a transcriptional network regulated by three core transcription factors: Nanog, Oct4, and Sox2 (reviewed in Silva and Smith, 2008; Nichols and Smith, 2009; Wray and Hartmann, 2012). Extrinsic signaling molecules including leukemia inhibitory factor (LIF) and Wnts influence the balance between pluripotency and differentiation in a context-dependent manner (Okita and Yamanaka, 2006; Loh et al., 2015). The primary consequence of Wnt stimulus is stabilization of β-catenin, a nuclear effector that activates transcription of target genes together with the lymphoid enhancer factor/T cell factor (TCF) family of transcription factors (Valenta et al., 2012). "
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    ABSTRACT: The ability of mouse embryonic stem cells (mESCs) to self-renew or differentiate into various cell lineages is regulated by signaling pathways and a core pluripotency transcriptional network (PTN) comprising Nanog, Oct4, and Sox2. The Wnt/β-catenin pathway promotes pluripotency by alleviating T cell factor TCF3-mediated repression of the PTN. However, it has remained unclear how β-catenin’s function as a transcriptional activator with TCF1 influences mESC fate. Here, we show that TCF1-mediated transcription is up-regulated in differentiating mESCs and that chemical inhibition of β-catenin/TCF1 interaction improves long-term self-renewal and enhances functional pluripotency. Genetic loss of TCF1 inhibited differentiation by delaying exit from pluripotency and conferred a transcriptional profile strikingly reminiscent of self-renewing mESCs with high Nanog expression. Together, our data suggest that β-catenin’s function in regulating mESCs is highly context specific and that its interaction with TCF1 promotes differentiation, further highlighting the need for understanding how its individual protein–protein interactions drive stem cell fate.
    The Journal of Cell Biology 10/2015; 211(1):39-52. · 9.83 Impact Factor
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    • "Undoubtedly, murine models are valuable proof-of-principle tools for biological and medical research but also have major limitations in predicting more complex physiological processes involving the immune system (Seok et al., 2013) or integration of transplanted cells into functional organs. Furthermore, it is not clear if the phenotypes of murine iPSCs and the molecular pathways maintaining selfrenewal are equivalent to those of human or nonhuman primate counterparts (Okita and Yamanaka, 2006; Rao, 2004; Schnerch et al., 2010). Because of their physiological similarities to humans, nonhuman primates can serve as a valuable translational research model in moving toward early phase clinical trials in humans. "
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    ABSTRACT: Induced pluripotent stem cell (iPSC)-based cell therapies have great potential for regenerative medicine but are also potentially associated with tumorigenic risks. Current rodent models are not optimal predictors of efficiency and safety for clinical application. Therefore, we developed a clinically relevant nonhuman primate model to assess the tumorigenic potential and in vivo efficacy of both undifferentiated and differentiated iPSCs in autologous settings without immunosuppression. Undifferentiated autologous iPSCs indeed form mature teratomas in a dose-dependent manner. However, tumor formation is accompanied by an inflammatory reaction. On the other hand, iPSC-derived mesodermal stromal-like cells form new bone in vivo without any evidence of teratoma formation. We therefore show in a large animal model that closely resembles human physiology that undifferentiated autologous iPSCs form teratomas, and that iPSC-derived progenitor cells can give rise to a functional tissue in vivo.
    Cell Reports 05/2014; 7(4). DOI:10.1016/j.celrep.2014.04.019 · 8.36 Impact Factor
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    • "These are grown and maintained on a feeder layer of mouse embryonic fibroblasts in a medium containing foetal bovine/calf serum, which may lead to unexpected viral infection and/or cross-species contamination. Thus, for human therapeutic applications, ES must be grown in a safe synthetic medium without factors or cells from other animals [12]. Owing to the above mentioned reasons we have used ES as the donor cells and differentiated them under serum free condition, in a synthetic medium and without any exogenous factors by the process of default neurogenesis [13]. "
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    ABSTRACT: We report here protection against rotenone-induced behavioural dysfunction, striatal dopamine depletion and nigral neuronal loss, following intra-striatal transplantation of neurons differentiated from murine embryonic stem cells (mES). mES maintained in serum free medium exhibited increase in neuronal, and decrease in stem cell markers by 7th and 10th days as revealed by RT-PCR and immunoblot analyses. Tyrosine hydroxylase, NURR1, PITX3, LMX1b and c-RET mRNA showed a significant higher expression in differentiated cells than in mES. Dopamine level was increased by 3-fold on 10th day as compared to 7 days differentiated cells. Severity of rotenone-induced striatal dopamine loss was attenuated, and amphetamine-induced unilateral rotations were significantly reduced in animals transplanted with 7 days differentiated cells, but not in animals that received undifferentiated ES transplant. However, the ratio of contralateral to ipsilateral swings in elevated body swing test was significantly reduced in both the transplanted groups, as compared to control. Striatal grafts exhibited the presence of tyrosine hydroxylase positive cells, and the percentage of dopaminergic neurons in the substantia nigra was also found to be higher in the ipsilateral side of 7 days and mES grafted animals. Increased expression of CD11b and IBA-1, suggested a significant contribution of these microglia-derived factors in controlling the limited survival of the grafted cells. Astrocytosis in the grafted striatum, and significant increase in the levels of glial cell line derived neurotrophic factor may have contributed to the recovery observed in the hemiparkinsonian rats following transplantation.
    PLoS ONE 09/2013; 8(9):e72501. DOI:10.1371/journal.pone.0072501 · 3.23 Impact Factor
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