A novel role for P2X7 receptor signalling in the survival of mouse embryonic stem cells

Thompson, Belinda A.N.; Storm, Michael P.; Hewinson, James; Hogg, Sarah; Welham, Melanie J.; Mackenzie, Amanda B.

doi:10.1016/j.cellsig.2011.11.012

Cited by 35 publications

(41 citation statements)

References 45 publications

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“…Indeed, ECs exhibit necrotic cell death in the context of exogenous millimolar levels of ATP, which is associated with chronic activation of P2X 7 receptors in ECs. 21 On the contrary, increasing evidence also presents for the pro-growth effect of P2X 7 receptors. In central nervous system, ATP exposure induces proliferation of neural stem cells (NSC) through the PI3k-kinase-dependent P70S6 kinase signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, that may further support that P2X 7 receptors exerting a pro-survival or pro-death effect depends on the mode of activation. 21 In brain gliomas, due to the highly aggressive, the interface between the glioma and normal appearance brain parenchyma is difficult to be truly recognized. With the invasion of glioma cells, the adjacent brain tissue is injured and ruined, these damaged area of gliomas has high concentration of extracellular ATP.…”

Section: Discussionmentioning

confidence: 99%

“…20 It is proposed that low levels of ATP in the extracellular milieu lead to the basal activation of P2X 7 receptors that couple to signaling pathways to promote cell survival. 21 Meanwhile, high concentration of extracellular ATP, the endogenous ligand of P2X 7 receptors, was reported in gliomas. 22 Therefore, it is possible that EPCs express P2X 7 receptors, activation of which could promote the proliferation and targeting ability of EPCs.…”

Section: Introductionmentioning

confidence: 99%

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The expression of P2X₇receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

Fang

Chen

Wang

et al. 2015

Cancer Biology & Therapy

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In order to use endothelial progenitor cells (EPCs) as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas, how to enhance proliferation and targeting ability of transplanted EPCs is a high priority. Here, we confirmed, for the first time, the expression of P2X 7 receptors in rat spleen-derived EPCs. Activation of P2X 7 receptors in EPCs by BzATP promoted cells proliferation and migration, rather than apoptosis. In vivo, the homing of transplanted EPCs after long-term suppression of P2X 7 receptors by persistent BBG stimulation was evaluated by MRI, immunohistochemistry and flow cytometry. Compared to the group without BBG treatment, less transplanted EPCs homed to gliomas in the group with BBG treatment, especially integrated into the vessels containing tumor-derived endothelial cells in gliomas. Moreover, western blot showed that CXCL1 expression was downregulated in gliomas with BBG treatment, which meant P2X 7 receptors suppression inhibited the homing of EPCs to gliomas through downregulation of CXCLl expression. Further, effects of P2X 7 receptors on C6 glioma cells or gliomas were evaluated at the same dose of BzATP or BBG used in EPCs experiments in vitro and in vivo. MTT assay and MRI revealed that P2X 7 receptors exerted no significant promoting effect on C6 glioma cells proliferation, gliomas growth and angiogenesis. Taken together, our findings imply the possibility of promoting proliferation and targeting ability of transplanted EPCs to brain gliomas in vivo through P2X 7 receptors, which may provide new perspectives on application of EPCs as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The expression of P2X₇receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

Fang

Chen

Wang

et al. 2015

Cancer Biology & Therapy

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“…51 Similarly, T lymphocytes secrete ATP, which stimulates P2X7 in an autocrine manner and induces IL-2 gene transcription and proliferation. 52 Several groups have described antiapoptotic and proliferationinducing effects of P2X7 in lymphoid cell lines, 61 embryonic stem cell cultures, 62 and microglia 63 in vitro as well as P2X7 tumor growth-promoting activity in vivo. 64 Such effects are associated with an increased cytoplasmic Ca 2ϩ concentration, activation of NFATc1, 65 and may be related to the expression of C-terminal truncated splice variants that lack the domain involved in pore formation.…”

Section: Extracellular Atp As Danger-associated Trigger For Immune Rementioning

confidence: 99%

Immunoregulation through extracellular nucleotides

Vitiello

Gorini

Rosano

et al. 2012

Blood

116

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Extracellular ATP (eATP), the most abundant among nucleotides, can act as a mediator during inflammatory responses by binding to plasmamembrane P2 purinergic receptors, which are widely expressed on cells of the immune system. eATP is generally considered as a classical danger signal, which stimulates immune responses in the presence of tissue damage. Converging evidence from several studies using murine models of chronic inflammation have supported this hypothesis; however, the role of eATP in the regulation of human immune function appears to be more complex. Chronic stimulation with micromolar eATP concentrations inhibits the proliferation of T and NK lymphocytes and enhances the capacity of dendritic cells to promote tolerance. The effect of eATP depends on multiple factors, such as the extent of stimulation, eATP concentration, presence/absence of other mediators in the microenvironment, and pattern of P2 receptor engagement.Small but significant differences in the pattern of P2 receptor expression in mice and humans confer the diverse capacities of ATP in regulating the immune response. Such diversity, which is often overlooked, should therefore be carefully considered when evaluating the role of eATP in human inflammatory and autoimmune diseases. (Blood. 2012;120(3): 511-518) Sources of eATPNucleotides are the constituents of nucleic acids, represent the energy store of the cell, and are involved in intracellular signaling as well as in cell-to-cell communication. 1 During the past 2 decades, increasing evidence has shown that extracellular ATP (eATP) is an important immune modulator. 2 ATP is present at relatively high levels in the cytoplasm of cells, where its concentration ranges from 1 to 10mM. In the extracellular space, its physiologic concentration is considerably lower, ranging between 1 and 10nM. Because of the steep concentration gradient as well as its small size and high mobility, ATP can be rapidly released together with other cellular components after mechanical stress, cell damage, or death. Increased ATP concentration in the extracellular milieu is therefore closely associated with tissue stress or damage. [3][4][5][6] However, nonlytic nucleotide release may occur in many cell types under a variety of conditions. Living cells in the steady-state release ATP through passive leakage. 7,8 Activated platelets represent a relevant source of ATP and release the nucleotide concomitantly with several inflammatory mediators during clot formation. 9 T lymphocytes release ATP during the early stages of activation through pannexin 1 (panx1) channels. 10 In addition, ATP is released during exercise from skeletal muscle as well as from vascular endothelial cells during conditions of increased blood flow or on mechanical stimulus. 11-13 Moreover, nonlytic ATP secretion from endothelial cells and leukocytes may be induced by pathogen-associated molecules, such as lipopolysaccharide. 14-17 ATP is also increased in draining lymph nodes during a contact hypersensitivity reaction. 18 ATP is released during ...

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“…It provides further evidence of the importance of ATP release and P2X7 receptors in mediating the differentiation direction of MSCs. Whilst this is the first demonstration of the involvement of the P2X7 receptor in human MSC, the P2X7 receptor has been previously shown to play a role in the balance of prosurvival or pro-death signals in mouse embryonic stem cells [5]. Indeed, the role of ATP and P2 receptors in stem cell biology is a fast expanding field with an emerging concept that the P2X7 receptor is responsible for regulating a fine balance between cell life and death [6].…”

Section: Commentarymentioning

confidence: 99%

Role of the P2X7 receptor in the osteogenic differentiation of mesenchymal cells and in osteoclast fusion

Wang

Gartland

2013

Purinergic Signalling

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The role of ATP and purinergic signalling in bone was proposed in the early 1990s [1]. Since then, expression of several P1 adenosine receptors and nearly all the P2 receptors has been reported on most of the cells of bone, with many studies demonstrating a fundamental role for purinergic signalling in bone cell biology. In the June issue of last year, Bronwen A. J. Evans presented an Highlight on the role of adenosine in bone formation, resorption and repair. In this issue, Ning Wang and Alison Gartland discuss two recently published papers which highlight the continued interest and unfolding involvement of P2X7 receptors in the processes that govern bone turnover. These are exciting times for purinergic signalling in bone given the impact bone disease has on the health and economy of increasingly ageing world population. Article summaryThis manuscript by Sun and colleagues implicate the importance of P2X7 receptors in the differentiation of mesenchymal stem cells towards bone forming osteoblasts [2]. In a series of well-designed and performed experiments, they tested and verified that 1) shockwaves induce ATP release from human mesenchymal stem cells (hMSCs), 2) shockwave-induced ATP release will activate P2X7 receptors and p38 MAP kinase (MAPK) signalling pathways, and 3) the downstream consequence of this enhanced osteogenic differentiation of hMSCs. The first part of this study verified that shockwave treatment could cause ATP release from hMSCs based on the previous observation of shockwave-induced ATP release from T cells [3]. Isolated hMSCs (validated as CD73 and CD105 positive and clean of contamination from CD34 and CD45 positive hematopoietic lineage cells) were treated with shockwaves and cell viability and ATP release assessed. When cells were subjected to >100 shockwave impulses significant release of ATP in the μM range was observed. However, >200 shockwave impulses induced significant extracellular ATP release but this was found to be due to shockwave induce cell damage. In the following part of the manuscript, the authors performed a set of experiments to test if shockwave treatment activates P2X7 receptors, p38 MAPK, and the downstream transcription factors c-fos and c-jun. Using western blotting, the phosphorylation of p38 MAPK of hMSCs were determined and found to be significantly enhanced either after shockwave treatment (<200 impulses) or exogenous ATP treatment (<100 μM). In addition, using real-time RT-PCR and immunocytochemical staining the expression of P2X7 receptors by the hMSCs was confirmed and found to be up-regulated following shockwaves treatment (100 impulses) and 1 μM exogenous ATP at both the mRNA and protein levels. Treating hMSCs with apyrase (an enzyme to hydrolyse extracellular ATP), P2X7-siRNA, PPADS (non-selective P2 antagonist), and KN-62 (P2X7 receptor antagonist) completely abolished the p38 MAPK activation induced by either shockwave or exogenous ATP treatment. These results confirmed that P2X7 receptors are involved in the shockwave and ATP

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A novel role for P2X7 receptor signalling in the survival of mouse embryonic stem cells

Cited by 35 publications

References 45 publications

The expression of P2X₇receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

The expression of P2X₇receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

Immunoregulation through extracellular nucleotides

Role of the P2X7 receptor in the osteogenic differentiation of mesenchymal cells and in osteoclast fusion

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A novel role for P2X7 receptor signalling in the survival of mouse embryonic stem cells

Cited by 35 publications

References 45 publications

The expression of P2X7receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

The expression of P2X7receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

Immunoregulation through extracellular nucleotides

Role of the P2X7 receptor in the osteogenic differentiation of mesenchymal cells and in osteoclast fusion

Contact Info

Product

Resources

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The expression of P2X₇receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

The expression of P2X₇receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas