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

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• 作者：Hongsen Peng ; Yunjie Hao ; Fatema Mousawi ; Sebastien Roger ; Jing Li ; Joan A. Sim ; Sreenivasan Ponnambalam ; Xuebin Yang and Lin-Hua Jiang
• 刊名：STEM CELLS
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：34
• 期：8
• 页码：2102-2114
• 全文大小：1437K
• ISSN：1549-4918

文摘

ATP is an extrinsic signal that can induce an increase in the cytosolic Ca²⁺ level ([Ca²⁺]_c) in mesenchymal stem cells (MSCs). However, the cognate intrinsic mechanisms underlying ATP-induced Ca²⁺ signaling in MSCs is still contentious, and their importance in MSC migration remains unknown. In this study, we investigated the molecular mechanisms underlying ATP-induced Ca²⁺ signaling and their roles in the regulation of cell migration in human dental pulp MSCs (hDP-MSCs). RT-PCR analysis of mRNA transcripts and interrogation of agonist-induced increases in the [Ca²⁺]_c support that P2X7, P2Y₁, and P2Y₁₁ receptors participate in ATP-induced Ca²⁺ signaling. In addition, following P2Y receptor activation, Ca²⁺ release-activated Ca²⁺ Orai1/Stim1 channel as a downstream mechanism also plays a significant role in ATP-induced Ca²⁺ signaling. ATP concentration-dependently stimulates hDP-MSC migration. Pharmacological and genetic interventions of the expression or function of the P2X7, P2Y₁ and P2Y₁₁ receptors, and Orai1/Stim1 channel support critical involvement of these Ca²⁺ signaling mechanisms in ATP-induced stimulation of hDP-MSC migration. Taken together, this study provide evidence to show that purinergic P2X7, P2Y₁, and P2Y₁₁ receptors and store-operated Orai1/Stim1 channel represent important molecular mechanisms responsible for ATP-induced Ca²⁺ signaling in hDP-MSCs 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