Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12 and increases the homing capacity and production of proinflammatory cytokines

Ferrari, Davide; Gulinelli, Sara; Salvestrini, Valentina; Lucchetti, Giovanna; Zini, Roberta; Manfredini, Rossella; Caione, Luisa; Piacibello, Wanda; Ciciarello, Marilena; Rossi, Lara; Idzko, Marco; Ferrari, Sérgio; Virgilio, Francesco Di; Lemoli, Roberto M.

doi:10.1016/j.exphem.2010.12.001

Cited by 72 publications

(128 citation statements)

References 31 publications

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“…Accumulating evidence shows that MSCs release ATP constitutively or in response to mechanical stimulation [17][18][19][20]. Previous studies consistently demonstrated that ATP induced robust Ca 21 responses but reported expression of a bewildering variety of P2X and P2Y receptors in MSCs from different tissues and species [17][18][19][20][21][22][23][24][25][26][27][28] and, as a result, the cognate intrinsic mechanisms remains contentious. There is also evidence for occurrence of storeoperated Ca 21 entry in BM-MSCs [17], but the molecular identity of the Ca 21 channels is still elusive.…”

Section: Introductionmentioning

confidence: 99%

“…ATP has been recognized as one of such extrinsic signals to raise the [Ca 21 ] c via activating multiple plasma membrane P2X and P2Y receptors [2][3][4][5][6]. ATP binding to the P2X receptors opens Ca 21 -permeable channels mediating extracellular Ca 21 influx. ATP can also elevate the [Ca 21 ] c via G a,q/11 -protein-coupled P2Y receptors, and more specifically, activation of the P2Y 1 , P2Y 2 , and P2Y 11 receptors in human cells stimulates phospholipase C-b (PLC-b) to generate inositol-1,4,5-triphosphate (IP 3 ), which in turn activates the IP 3 receptor and induces Ca 21 release from the endoplasmic reticulum (ER).…”

Section: Introductionmentioning

confidence: 99%

“…ATP can also elevate the [Ca 21 ] c via G a,q/11 -protein-coupled P2Y receptors, and more specifically, activation of the P2Y 1 , P2Y 2 , and P2Y 11 receptors in human cells stimulates phospholipase C-b (PLC-b) to generate inositol-1,4,5-triphosphate (IP 3 ), which in turn activates the IP 3 receptor and induces Ca 21 release from the endoplasmic reticulum (ER). Reduction in the ER Ca 21 level can further induce store-operated Ca 21 entry through the Ca 21 release-activated Ca 21 (CRAC) a channels [7,8]. Mesenchymal stem cells (MSCs) exhibit an ability to differentiate into osteoblasts, adipocytes, and chondrocytes [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Calcium ion (Ca 21 ) is a ubiquitous intracellular messenger that has a crucial role in determining a plethora of cellular functions such as proliferation, migration, differentiation, and communication, and mammalian cells express numerous intrinsic mechanisms responding to various extrinsic signals with specific increases in the cytosolic Ca 21 level ([Ca 21 ] c ) and forming diverse cellular Ca 21 signatures with distinct spatial and temporal dynamics [1]. ATP has been recognized as one of such extrinsic signals to raise the [Ca 21 ] c via activating multiple plasma membrane P2X and P2Y receptors [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Purinergic and Store-Operated Ca2+ Signaling Mechanisms in Mesenchymal Stem Cells and Their Roles in ATP-Induced Stimulation of Cell Migration

et al. 2016

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Orai1/Stim1 channel as a downstream mechanism also plays a significant role in ATP-induced Ca 21 signaling. ATP concentration-dependently stimulates hDP-MSC migration. Pharmacological and genetic interventions of the expression or function of the P2X7, P2Y 1 and P2Y 11 receptors, and Orai1/Stim1 channel support critical involvement of these Ca 21 signaling mechanisms in ATP-induced stimulation of hDP-MSC migration. Taken together, this study provide evidence to show that purinergic P2X7, P2Y 1 , and P2Y 11 receptors and store-operated Orai1/Stim1 channel represent important molecular mechanisms responsible for ATP-induced Ca 21 signaling in hDPMSCs and activation of these mechanisms stimulates hDP-MSC migration. Such information is useful in building a mechanistic understanding of MSC homing in tissue homeostasis and developing more efficient MSC-based therapeutic applications. STEM CELLS 2016;34:2102-2114 SIGNIFICANCE STATEMENTATP is an important signaling molecule that regulates diverse cell functions. Mesenchymal stem cells (MSCs) have promising potential of therapeutic application but the migration capacity of MSCs limits the effectiveness of MSC-based therapies. MSCs release ATP and here we provide evidence to show that ATP stimulates MSC migration through purinergic P2X7, P2Y 1 , and P2Y 11 receptors. Our study is the first to find that Orai1 and Sitm1 form Ca 21 -release-activated-Ca 21 channel as downstream Ca 21 signaling mechanism mediating ATP-induced stimulation of MSC migration. These results reveal novel mechanisms regulating MSC migration. Such information is desirable in optimization of MSC cultures for therapeutic use.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Purinergic and Store-Operated Ca2+ Signaling Mechanisms in Mesenchymal Stem Cells and Their Roles in ATP-Induced Stimulation of Cell Migration

et al. 2016

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“…Human MSCs express all P2Y receptors and the P2X3-7 receptors [291,292]. Recently, extracellular nucleotides have been reported to modulate the differentiation of human MSCs, with the P2X6, P2Y 4 and P2Y 14 receptors identified as playing pivotal roles in this process [292,293]. UDP activation of P2Y 6 receptors has also been shown to regulate the osteogenic differentiation of the primary MSCs from postmenopausal women [291].…”

Section: Bone Marrow Stromal Cells or Mesenchymal Stem Cellsmentioning

confidence: 99%

Purinergic signalling in the musculoskeletal system

Burnstock

Arnett

Orriss

2013

Purinergic Signalling

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114

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It is now widely recognised that extracellular nucleotides, signalling via purinergic receptors, participate in numerous biological processes in most tissues. It has become evident that extracellular nucleotides have significant regulatory effects in the musculoskeletal system. In early development, ATP released from motor nerves along with acetylcholine acts as a cotransmitter in neuromuscular transmission; in mature animals, ATP functions as a neuromodulator. Purinergic receptors expressed by skeletal muscle and satellite cells play important pathophysiological roles in their development or repair. In many cell types, expression of purinergic receptors is often dependent on differentiation. For example, sequential expression of P2X5, P2Y 1 and P2X2 receptors occurs during muscle regeneration in the mdx model of muscular dystrophy. In bone and cartilage cells, the functional effects of purinergic signalling appear to be largely negative. ATP stimulates the formation and activation of osteoclasts, the bone-destroying cells. Another role appears to be as a potent local inhibitor of mineralisation. In osteoblasts, the bone-forming cells, ATP acts via P2 receptors to limit bone mineralisation by inhibiting alkaline phosphatase expression and activity. Extracellular ATP additionally exerts significant effects on mineralisation via its hydrolysis product, pyrophosphate. Evidence now suggests that purinergic signalling is potentially important in several bone and joint disorders including osteoporosis, rheumatoid arthritis and cancers. Strategies for future musculoskeletal therapies might involve modulation of purinergic receptor function or of the ecto-nucleotidases responsible for ATP breakdown or ATP transport inhibitors.

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Reconciling the stem cell and paracrine paradigms of mesenchymal stem cell function

Boregowda

Phinney

2016

The Biology and Therapeutic Application of Mesenchymal Cells

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Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12 and increases the homing capacity and production of proinflammatory cytokines

Cited by 72 publications

References 31 publications

Purinergic and Store-Operated Ca2+ Signaling Mechanisms in Mesenchymal Stem Cells and Their Roles in ATP-Induced Stimulation of Cell Migration

Purinergic and Store-Operated Ca2+ Signaling Mechanisms in Mesenchymal Stem Cells and Their Roles in ATP-Induced Stimulation of Cell Migration

Purinergic signalling in the musculoskeletal system

Reconciling the stem cell and paracrine paradigms of mesenchymal stem cell function

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