Phosphoinositide 3-kinases and regulation of embryonic stem cell fate

Department of Pharmacy and Pharmacology and The Centre for Regenerative Medicine, University of Bath, Claverton Down, Bath, UK.
Biochemical Society Transactions (Impact Factor: 3.19). 05/2007; 35(Pt 2):225-8. DOI: 10.1042/BST0350225
Source: PubMed


ES (embryonic stem) cell lines are derived from the epiblast of pre-implantation embryos and like the inner cell mass cells from which they are derived exhibit the remarkable property of pluripotency, namely the ability to differentiate into all cell lineages comprising the adult organism. ES cells and their differentiated progeny offer tremendous potential to regenerative medicine, particularly as cellular therapies for the treatment of a wide variety of chronic disorders, such as Type 1 diabetes, Parkinson's disease and retinal degeneration. In order for this potential to be realized, a detailed understanding of the molecular mechanisms regulating the fundamental properties of ES cells, i.e. pluripotency, proliferation and differentiation, is required. In the present paper, we review the evidence that PI3K (phosphoinositide 3-kinase)-dependent signalling plays a role in regulation of both ES cell pluripotency and proliferation.

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    • "Identifying the various factors that sustain self-renewal and preserve multilineage differentiation of both human and mouse stem cells is an active area of stem cell research. Several signaling pathways have been shown to play important roles in stem cell and cancer stem cell development including: PI3K (Welham et al., 2007), Wnt (Sato et al., 2004), fibroblast growth factor (FGF) (Dvorak et al., 2006), bone morphogenic protein (BMP) (Ying et al., 2003), transforming growth factor (TGF)-b (James et al., 2005) Notch (Carlson and Conboy, 2007), and Hedgehog (Peacock et al., 2007). PI3K pathway components cross-talk with each of these other pathways and several of these interactions are described in more detail below as they relate to ES cell maintenance and cancer. "
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    ABSTRACT: The capacity of embryonic stem (ES) cells to differentiate into cell lineages comprising the three germ layers makes them powerful tools for studying mammalian early embryonic development in vitro. The human body consists of approximately 210 different somatic cell types, the majority of which have limited proliferative capacity. However, both stem cells and cancer cells bypass this replicative barrier and undergo symmetric division indefinitely when cultured under defined conditions. Several signal transduction pathways play important roles in regulating stem cell development, and aberrant expression of components of these pathways is linked to cancer. Among signaling systems, the critical role of leukemia inhibitory factor (LIF) coupled to the Jak/STAT3 (signal transduction and activation of transcription-3) pathway in maintaining stem cell self-renewal has been extensively reviewed. This pathway additionally plays multiple roles in tumorigenesis. Likewise, the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) pathway has been determined to play an important role in both stem cell maintenance and tumor development. This pathway is often induced in cancer with frequent mutational activation of the catalytic subunit of PI3K or loss of a primary PI3K antagonist, phosphatase and tensin homolog deleted on chromosome ten (PTEN). This review focusses on roles of the PI3K signal transduction pathway components, with emphasis on functions in stem cell maintenance and cancer. Since the PI3K pathway impinges on and collaborates with other signaling pathways in regulating stem cell development and/or cancer, aspects of the canonical Wnt, Ras/mitogen-activated protein kinase (MAPK), and TGF-β signaling pathways are also discussed. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 10/2014; 229(10). DOI:10.1002/jcp.24603 · 3.84 Impact Factor
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    • "Altogether, these observations would suggest the dispensability of LIF in supporting pluripotency in the porcine species and would seem to disagree with our results indicating LIF as an important factor, supporting both attachment and self-renewal. Further molecular characterization, however , indicated the possibility that this cytokine is unlikely to act through the gp130 ⁄ LIFR ⁄ STAT3 signalling pathway, but rather via an alternative cascade involving phosphoinositide-3 kinase (PI3K), serine ⁄ threonine protein kinase (AKT) (a key effector in the PI3K pathway) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (a negative regulator of the same pathway) (Fig. 3), known to be responsive to LIF and has been previously shown to trigger the expression of NANOG and to facilitate efficient proliferation and survival of murine ESCs (Welham et al. 2007). As mentioned previously, pig outgrowth attachment and colony formation were also encouraged by bFGF, which has been reported to be necessary for proliferation and pluripotency (Mummery et al. 1993; Levenstein et al. 2006) and to fully replace LIF for maintenance of human ESCs self-renewal (Xu et al. 2005b). "
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    ABSTRACT: Huge amounts of work have been dedicated to the establishment of embryonic stem cell lines from farm animal species since the successful isolation of embryonic stem cells from the mouse and from the human. However, no conclusive results have been obtained so far, and validated lines have yet to be established in domestic animals. Many limiting factors have been suggested and need to be studied further to isolate truly pluripotent cell lines from livestock. In this review, we will discuss the difficulties in deriving and maintaining embryonic stem cell lines from farm animal embryos and how can this lack of success be explained. We will summarize results obtained in our laboratory regarding derivation of pluripotent cells in the pigs. Problems related to the identification of standard methods for derivation, maintenance and characterization of cell lines will also be examined. We will focus our attention on the need for appropriate stemness-related marker molecules that can be used to reliably investigate pluripotency in domestic species. Finally, we will review data presently available on functional key pluripotency-maintaining pathways in farm animals.
    Reproduction in Domestic Animals 08/2012; 47 Suppl 4(s4):86-91. DOI:10.1111/j.1439-0531.2012.02060.x · 1.52 Impact Factor
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    • "A closer look to the gene expression pattern of our lines showed the expression of three genes (PI3K, AKT and PTEN), representative of the PI3- K ⁄ AKT pathway, which is also known to be responsive to LIF (Brevini et al. 2010). The activation of this pathways by LIF upregulates NANOG and facilitates efficient proliferation and survival of murine ESC (Welham et al. 2007). This observation is not in contrast with the role of FGF2 because this molecule can also bind and activate the PI3K ⁄ AKT cascade (Jirmanova et al. 2002; Xu et al. 2005). "
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    ABSTRACT: Pluripotent stem cells are the focus of an extremely active field of investigation that is bringing new light on our understanding of the mechanisms that control pluripotency and differentiation. Rodent and primates are the only species where true, or bona fide, pluripotent stem cells have been derived. The attempts to derive pluripotent stem cells from domestic ungulates have been going on for more than 20 years with little progress. Cell lines from these species present a series of limitations that have precluded their use for both basic and clinically oriented studies. However, in the last 3 years, some substantial progress have been made making the currently available ungulate pluripotent stem cells closest than ever before to their human and mouse counterpart. This result has been achieved through both conceptual and technical progress that will be illustrated and discussed in this review.
    Reproduction in Domestic Animals 08/2012; 47 Suppl 5(s5):11-7. DOI:10.1111/j.1439-0531.2012.02106.x · 1.52 Impact Factor
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