Role of Gap Junctions in Embryonic and Somatic Stem Cells

Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
Stem cell reviews (Impact Factor: 2.77). 09/2008; 4(4):283-92. DOI: 10.1007/s12015-008-9038-9
Source: PubMed


Stem cells provide an invaluable tool to develop cell replacement therapies for a range of serious disorders caused by cell damage or degeneration. Much research in the field is focused on the identification of signals that either maintain stem cell pluripotency or direct their differentiation. Understanding how stem cells communicate within their microenvironment is essential to achieve their therapeutic potentials. Gap junctional intercellular communication (GJIC) has been described in embryonic stem cells (ES cells) and various somatic stem cells. GJIC has been implicated in regulating different biological events in many stem cells, including cell proliferation, differentiation and apoptosis. This review summarizes the current understanding of gap junctions in both embryonic and somatic stem cells, as well as their potential role in growth control and cellular differentiation.

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Available from: Raymond Wong, May 14, 2015
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    • "ES cells are actively proliferating cells with a relatively short cell cycle (see Supplemental Movie 1). They can infinitely self-renew while maintaining their pluripotency that is mediated via GJIC among the cells in the colony [27] [28] [29]. Treatment of mES cells with EGF is known to down-regulate GJIC [30]. "
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    ABSTRACT: Gap junctions (GJ) traverse apposing membranes of neighboring cells to mediate intercellular communication by passive diffusion of signaling molecules. We have shown previously that cells endocytose GJs utilizing the clathrin machinery. Endocytosis generates cytoplasmic double-membrane vesicles termed annular gap junctions or connexosomes. However, the signaling pathways and protein modifications that trigger GJ endocytosis are largely unknown. Treating mouse embryonic stem cell colonies - endogenously expressing the GJ protein connexin43 (Cx43) - with epidermal growth factor (EGF) inhibited intercellular communication by 64% and activated both, MAPK and PKC signaling cascades to phosphorylate Cx43 on serines 262, 279/282, and 368. Upon EGF treatment Cx43 phosphorylation transiently increased up to 4 fold and induced efficient (66.4%) GJ endocytosis as evidenced by a 5.9 fold increase in Cx43/clathrin co-precipitation.
    Preview · Article · Jan 2014 · FEBS letters
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    • "For example, metabolic products such as melanin, which are resistant to degradation [47], may not be a reliable indicator of the lack of lineage conversion as they may persist long after the expression of genes associated with their biosynthesis has been attenuated. Also, the presence of stem cell properties and epithelial features such as the presence of adherence junctions, tight junctions, and gap junctions are not mutually exclusive; neuroepithelium and their stem cell derivatives possess these features and their role in the regulation of stem cells, both embryonic and somatic, has begun to emerge [4,48-50]. The presence of morphological features of differentiated cells such as microvilli may not be an exclusionary criterion [26] either, given the evidence that some stem cells, embryonic [51,52] and somatic [53,54] display such features. "
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    ABSTRACT: The neural stem cells discovered in the adult ciliary epithelium (CE) in higher vertebrates have emerged as an accessible source of retinal progenitors; these cells can self-renew and possess retinal potential. However, recent studies have cast doubt as to whether these cells could generate functional neurons and differentiate along the retinal lineage. Here, we have systematically examined the pan neural and retinal potential of CE stem cells. Molecular and cellular analysis was carried out to examine the plasticity of CE stem cells, obtained from mice expressing green fluorescent protein (GFP) under the influence of the promoter of the rod photoreceptor-specific gene, Nrl, using the neurospheres assay. Differentiation was induced by specific culture conditions and evaluated by both transcripts and protein levels of lineage-specific regulators and markers. Temporal pattern of their levels were examined to determine the expression of genes and proteins underlying the regulatory hierarchy of cells specific differentiation in vitro. Functional attributes of differentiation were examined by the presence of current profiles and pharmacological mobilization of intracellular calcium using whole cell recordings and Fura-based calcium imaging, respectively. We demonstrate that stem cells in adult CE not only have the capacity to generate functional neurons, acquiring the expression of sodium and potassium channels, but also respond to specific cues in culture and preferentially differentiate along the lineages of retinal ganglion cells (RGCs) and rod photoreceptors, the early and late born retinal neurons, respectively. The retinal differentiation of CE stem cells was characterized by the temporal acquisition of the expression of the regulators of RGCs and rod photoreceptors, followed by the display of cell type-specific mature markers and mobilization of intracellular calcium. Our study demonstrates the bonafide retinal potential of adult CE stem cells and suggests that their plasticity could be harnessed for clinical purposes once barriers associated with any lineage conversion, i.e., low efficiency and fidelity is overcome through the identification of conducive culture conditions.
    Full-text · Article · Oct 2013 · BMC Neuroscience
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    • "To date, 21 members of the connexin gene family have been identified in the human genome [36]. Of these, and as noted above, Cx43 is highly expressed in undifferentiated hESCs [37]. However, no information is available regarding GJIC between hESCs and human feeder cells. "
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    ABSTRACT: Human embryonic stem cells (hESCs) are a promising and powerful source of cells for applications in regenerative medicine, tissue engineering, cell-based therapies, and drug discovery. Many researchers have employed conventional culture techniques using feeder cells to expand hESCs in significant numbers, although feeder-free culture techniques have recently been developed. In regard to stem cell expansion, gap junctional intercellular communication (GJIC) is thought to play an important role in hESC survival and differentiation. Indeed, it has been reported that hESC-hESC communication through connexin 43 (Cx43, one of the major gap junctional proteins) is crucial for the maintenance of hESC stemness during expansion. However, the role of GJIC between hESCs and feeder cells is unclear and has not yet been reported. This study therefore examined whether a direct Cx43-mediated interaction between hESCs and human adipose-derived stem cells (hASCs) influences the maintenance of hESC stemness. Over 10 passages, hESCs cultured on a layer of Cx43-downregulated hASC feeder cells showed normal morphology, proliferation (colony growth), and stemness, as assessed by alkaline phosphatase (AP), OCT4 (POU5F1-Human gene Nomenclature Database), SOX2, and NANOG expression. These results demonstrate that Cx43-mediated GJIC between hESCs and hASC feeder cells is not an important factor for the conservation of hESC stemness and expansion.
    Full-text · Article · Jul 2013 · PLoS ONE
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