Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signaling

Abstract

In this study, we examined the Ca2+‐permeable Piezo1 channel, a newly identified mechanosensing ion channel, in human dental pulp‐derived mesenchymal stem cells (MSCs) and hypothesized that activation of the Piezo1 channel regulates MSC migration via inducing ATP release and activation of the P2 receptor purinergic signaling. The Piezo1 mRNA and protein were readily detected in hDP‐MSCs from multiple donors and, consistently, brief exposure to Yoda1, the Piezo1 channel‐specific activator, elevated intracellular Ca2+ concentration. Yoda1‐induced Ca2+ response was inhibited by ruthenium red or GsMTx4, two Piezo1 channel inhibitors, and also by Piezo1‐specific siRNA. Brief exposure to Yoda1 also induced ATP release. Persistent exposure to Yoda1 stimulated MSC migration, which was suppressed by Piezo1‐specific siRNA, and also prevented by apyrase, an ATP scavenger, or PPADS, a P2 generic antagonist. Furthermore, stimulation of MSC migration induced by Yoda1 as well as ATP was suppressed by PF431396, a PYK2 kinase inhibitor, or U0126, an inhibitor of the mitogen‐activated protein kinase MEK/ERK signaling pathway. Collectively, these results suggest that activation of the Piezo1 channel stimulates MSC migration via inducing ATP release and subsequent activation of the P2 receptor purinergic signaling and downstream PYK2 and MEK/ERK signaling pathways, thus revealing novel insights into the molecular and signaling mechanisms regulating MSC migration. Such findings provide useful information for evolving a full understanding of MSC migration and homing and developing strategies to improve MSC‐based translational applications.

The Mechanical Microenvironment in Breast Cancer

“…For example, force stimulated Ca 2+ flux through piezo channels can stimulate vasculature architectural organization and cell polarity [ 87 ] or epithelial cell division [ 17 ]. Piezo specific Ca 2+ signaling can also drive stem cell migration [ 88 ], the formation of focal adhesions [ 89 ], or cell cycle progression [ 90 ]. For integrins, forces via increased substrate stiffness can lead to the formation of integrin and focal adhesion kinase rich mature cell adhesions [ 62 ].…”

Adenosine Triphosphate Release and P2 Receptor Signaling in Piezo1 Channel-Dependent Mechanoregulation

“…A more recent study shows that shockwave-induced ATP release via undefined release mechanisms and subsequent activation of the P2X7 receptor stimulated osteogenic differentiation (Sun et al, 2013). The expression of the Piezo1 channel has been documented in several very recent studies using MSCs from different species and tissues (Gao et al, 2017; Sugimoto et al, 2017; Mousawi et al, 2019). Our recent study shows that Yoda1-induced activation of the Piezo1 channel in human dental pulp MSC promoted migration, which was suppressed by siRNA-mediated knockdown of the Piezo1 expression (Mousawi et al, 2019).…”

“…The expression of the Piezo1 channel has been documented in several very recent studies using MSCs from different species and tissues (Gao et al, 2017; Sugimoto et al, 2017; Mousawi et al, 2019). Our recent study shows that Yoda1-induced activation of the Piezo1 channel in human dental pulp MSC promoted migration, which was suppressed by siRNA-mediated knockdown of the Piezo1 expression (Mousawi et al, 2019). More importantly, Yoda1-induced activation of the Piezo1 channel stimulated ATP release from human dental pulp MSCs (Mousawi et al, 2019).…”

“…The expression of the Piezo1 channel has been shown in an increasing number of cell types in various tissues and organs, including neurons, astrocytes, smooth muscle cells, endothelial cells, epithelial cells, red blood cells, immune cells, periodontal ligament cells, neural progenitor cells, mesenchymal stem cells, and embryonic stem cells (e.g., Li et al, 2014; Pathak et al, 2014; Jin et al, 2015; Gudipaty et al, 2017; Murthy et al, 2017; Del Marmol et al, 2018; Friedrich et al, 2019; Mousawi et al, 2019; Solis et al, 2019; Song et al, 2019; Velasco-Estevez et al, 2019). The Piezo1 channel is mainly located in the plasma membrane (Coste et al, 2010; Coste et al, 2012; Miyamoto et al, 2014; Hung et al, 2016).…”

“…Some evidence suggests that the Piezo1 channel is also present in the membrane of endoplasmic reticulum (McHugh et al, 2010) and in the cytoplasmic compartments near the nucleus (Miyamoto et al, 2014) and nuclear envelope (Gudipaty et al, 2017). A large number of recent studies have disclosed a critical role for the cell surface Piezo1 channel or, more specifically, Piezo1-mediated Ca 2+ influx, in the regulation of a multiple of cell functions (e.g., Li et al, 2014; Pathak et al, 2014; Cinar et al, 2015; Hung et al, 2016; Gudipaty et al, 2017; Del Marmol et al, 2018; Friedrich et al, 2019; Mousawi et al, 2019; Solis et al, 2019; Song et al, 2019; Velasco-Estevez et al, 2019; see a recent review by Xiao, 2019). As discussed next, accumulating evidence supports that ATP release and subsequent activation of the P2X and/or P2Y receptors are critical in mediating Piezo1 channel-dependent mechanoregulation.…”