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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    • "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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    • "Despite these reports, the exact role of PPAR␥ in the maintenance and differentiation of mESCs in the presence and absence of LIF remains to be elucidated and it is suggested that further experiments using knock down of PPAR␥ need to be conducted. To our knowledge, LIF maintains self-renewal and pluripotency of mESCs through activation of the JAK/STAT signaling pathway while removal of LIF from the culture media induces spontaneous differentiation into different cell lineages via the ERK pathway (Okita and Yamanaka, 2006). To evaluate the role of PPAR␥ on mESCs proliferation, we assessed proliferation of mESCs in the presence and absence of LIF. "
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    ABSTRACT: The aim of this study was to evaluate the influence of peroxisome proliferator-activated receptor � (PPAR�) on self-renewal of mouse embryonic stem cells (mESCs) in the presence and absence of leukemia inhibitory factor (LIF). We demonstrated that in the presence of LIF, the activation of PPAR� by Rosiglitazone led to an increased proliferation of mESCs whereas PPAR� antagonist (GW9662) reversed this effect. Additionally, upon PPAR� activation, LIF increased PPAR� expression and resulted in the degradation of suppressor of cytokine signaling 3 (SOCS3), an important negative regulator of LIF/signal transducers and activators of transcription 3 (STAT3)-pathway. In the absence of LIF, Rosiglitazone decreased proliferation of mESCs. In this state, our results showed that extracellular signal-regulated kinase (ERK) proteins were activated and resulted in the suppression of Nanog expression, an important pluripotency determinant, whereas it did not affect Oct4 expression. These results suggest that the pivotal role of PPAR� on mESC self-renewal depends on the presence and absence of LIF.
    European Journal of Cell Biology 03/2013; 92:160-168. · 3.83 Impact Factor
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