Low-Intensity Ultrasound Modulates Ca²⁺ Dynamics in Human Mesenchymal Stem Cells via Connexin 43 Hemichannel

In recent years, ultrasound has gained attention in new biological applications due to its ability to induce specific biological responses at the cellular level. Although the biophysical mechanisms underlying the interaction between ultrasound and cells are not fully understood, many agree on a pivotal role of Ca²⁺ signaling through mechanotransduction pathways. Because Ca²⁺ regulates a vast range of downstream cellular processes, a better understanding of how ultrasound influences Ca²⁺ signaling could lead to new applications for ultrasound. In this study, we investigated the mechanism of ultrasound-induced Ca²⁺ mobilization in human mesenchymal stem cells using 47 MHz focused ultrasound to stimulate single cells at low intensities (~ 110 mW/cm²). We found that ultrasound exposure triggers opening of connexin 43 hemichannels on the plasma membrane, causing release of ATP into the extracellular space. That ATP then binds to G-protein-coupled P₂Y₁ purinergic receptors on the membrane, in turn activating phospholipase C, which evokes production of inositol trisphosphate and release of Ca²⁺ from intracellular stores.