Coupling switch of P2Y-IP3 receptors mediates differential Ca2+ signaling in human embryonic stem cells and derived cardiovascular progenitor cells

Huang, Jingsong; Zhang, Min; Zhang, Peng; Liang, He; Ouyang, Kunfu; Yang, Huang‐Tian

doi:10.1007/s11302-016-9512-9

Cited by 12 publications

(14 citation statements)

References 55 publications

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“…This in vitro differentiation system is being explored for cardiac regenerative therapy. 228 All cells in the vascular system express one or more types of purine or pyrimidine receptors, so this raises the possibility that purine receptors may be potential targets in vascular disease. 24,229 ATP release mechanisms, receptors, and ectonucleotidases are all potential targets for drug development for treatment of vascular diseases such as hypertension, atherosclerosis, and thrombosis.…”

Section: Perspectives and Future Directionsmentioning

confidence: 99%

Purinergic Signaling in the Cardiovascular System

Burnstock

2017

Circulation Research

331

295

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Abstract:There is nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory-motor nerves, as well as in intracardiac neurons. Centers in the brain control heart activities and vagal cardiovascular reflexes involve purines. Adenine nucleotides and nucleosides act on purinoceptors on cardiomyocytes, AV and SA nodes, cardiac fibroblasts, and coronary blood vessels. Vascular tone is controlled by a dual mechanism. ATP, released from perivascular sympathetic nerves, causes vasoconstriction largely via P2X1 receptors. Endothelial cells release ATP in response to changes in blood flow (via shear stress) or hypoxia, to act on P2 receptors on endothelial cells to produce nitric oxide, endothelium-derived hyperpolarizing factor, or prostaglandins to cause vasodilation. ATP is also released from sensory-motor nerves during antidromic reflex activity, to produce relaxation of some blood vessels. Purinergic signaling is involved in the physiology of erythrocytes, platelets, and leukocytes. ATP is released from erythrocytes and platelets, and purinoceptors and ectonucleotidases are expressed by these cells. P1, P2Y 1 , P2Y 12 , and P2X1 receptors are expressed on platelets, which mediate platelet aggregation and shape change. Long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides promote migration and proliferation of vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis, vessel remodeling during restenosis after angioplasty and atherosclerosis. The involvement of purinergic signaling in cardiovascular pathophysiology and its therapeutic potential are discussed, including heart failure, infarction, arrhythmias, syncope, cardiomyopathy, angina, heart transplantation and coronary bypass grafts, coronary artery disease, diabetic cardiomyopathy, hypertension, ischemia, thrombosis, diabetes mellitus, and migraine. (Circ Res. 2017;120:207-228.

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Section: Perspectives and Future Directionsmentioning

confidence: 99%

Purinergic Signaling in the Cardiovascular System

Burnstock

2017

Circulation Research

331

295

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“…hESC culture hESC culture was carried out as described previously [5,13] . Briefly, hESC lines H7 and H9 (WiCell Research Institute, Madison, WI, USA) were routinely maintained in mTeSR1 medium (Stem Cell Technologies, Vancouver, Canada) on Matrigel-coated dishes (hESC qualified; Corning, New York, NY, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Ca 2+ imaging hESCs were loaded with 2.5 µmol/L Fluo4-AM (Life Technologies, South San Francisco, CA, USA) as reported previously [5] . Briefly, the Fluo 4-AM was dissolved in the extracellular bath solution for 30 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we and others have found that Ca 2+ signals are triggered by purinergic stimulation in hESCs [5,7,9] . We further demonstrated that this effect is mediated via the purinergic receptor P2Y1-IP 3 R2 pathway [5] . However, the properties of the Ca 2+ -handling machinery in hESCs are largely unknown.…”

Section: Introductionmentioning

confidence: 90%

“…They have been widely studied as models of early development, in drug screening and as potential candidates in cell therapy in recent years [1][2][3][4] . Emerging evidence suggests that the calcium ion (Ca 2+ ) is an important second messenger involved in the maintenance of the pluripotency and self-renewal of hESCs and takes part in the differentiation of these cells [5][6][7][8][9] . However, little is known about the physiological and pharmacological properties of Ca 2+ signaling and how the intracellular free Ca 2+ concentration ([Ca 2+ ] i ) is regulated in hESCs.…”

Section: Introductionmentioning

confidence: 99%

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Functional expression of the Ca2+ signaling machinery in human embryonic stem cells

et al. 2017

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Emerging evidence suggests that Ca signals are important for the self-renewal and differentiation of human embryonic stem cells (hESCs). However, little is known about the physiological and pharmacological properties of the Ca-handling machinery in hESCs. In this study we used RT-PCR and Western blotting to analyze the expression profiles of genes encoding Ca-handling proteins; we also used confocal Ca imaging and pharmacological approaches to determine the contribution of the Ca-handling machinery to the regulation of Ca signaling in hESCs. We revealed that hESCs expressed pluripotent markers and various Ca-handling-related genes. ATP-induced Ca transients in almost all hESCs were inhibited by the inositol-1,4,5-triphosphate receptor (IPR) blocker 2-APB or xestospongin C. In addition, Ca transients were induced by a ryanodine receptor (RyR) activator, caffeine, in 10%-15% of hESCs and were blocked by ryanodine, whereas caffeine and ATP did not have additive effects. Moreover, store-operated Ca entry (SOCE) but not voltage-operated Ca channel-mediated Ca entry was observed. Inhibition of sarco/endoplasmic reticulum (ER) Ca-ATPase (SERCA) by thapsigargin induced a significant increase in the cytosolic free Ca concentration ([Ca]). For the Ca extrusion pathway, inhibition of plasma membrane Ca pumps (PMCAs) by carboxyeosin induced a slow increase in [Ca], whereas the Na/Ca exchanger (NCX) inhibitor KBR7943 induced a rapid increase in [Ca]. Taken together, increased [Ca] is mainly mediated by Ca release from intracellular stores via IP3Rs. In addition, RyRs function in a portion of hESCs, thus indicating heterogeneity of the Ca-signaling machinery in hESCs; maintenance of low [Ca] is mediated by uptake of cytosolic Ca into the ER via SERCA and extrusion of Ca out of cells via NCX and PMCA in hESCs.

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hESC‐Derived Epicardial Cells Promote Repair of Infarcted Hearts in Mouse and Swine

Luo,

Jiang,

et al. 2023

Advanced Science

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Myocardial infarction (MI) causes excessive damage to the myocardium, including the epicardium. However, whether pluripotent stem cell‐derived epicardial cells (EPs) can be a therapeutic approach for infarcted hearts remains unclear. Here, the authors report that intramyocardial injection of human embryonic stem cell‐derived EPs (hEPs) at the acute phase of MI ameliorates functional worsening and scar formation in mouse hearts, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis. Mechanistically, hEPs suppress MI‐induced infiltration and cytokine‐release of inflammatory cells and promote reparative macrophage polarization. These effects are blocked by a type I interferon (IFN‐I) receptor agonist RO8191. Moreover, intelectin 1 (ITLN1), abundantly secreted by hEPs, interacts with IFN‐β and mimics the effects of hEP‐conditioned medium in suppression of IFN‐β‐stimulated responses in macrophages and promotion of reparative macrophage polarization, whereas ITLN1 downregulation in hEPs cancels beneficial effects of hEPs in anti‐inflammation, IFN‐I response inhibition, and cardiac repair. Further, similar beneficial effects of hEPs are observed in a clinically relevant porcine model of reperfused MI, with no increases in the risk of hepatic, renal, and cardiac toxicity. Collectively, this study reveals hEPs as an inflammatory modulator in promoting infarct healing via a paracrine mechanism and provides a new therapeutic approach for infarcted hearts.

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Coupling switch of P2Y-IP3 receptors mediates differential Ca2+ signaling in human embryonic stem cells and derived cardiovascular progenitor cells

Cited by 12 publications

References 55 publications

Purinergic Signaling in the Cardiovascular System

Purinergic Signaling in the Cardiovascular System

Functional expression of the Ca2+ signaling machinery in human embryonic stem cells

hESC‐Derived Epicardial Cells Promote Repair of Infarcted Hearts in Mouse and Swine

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