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

Abstract

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 Ca signaling through mechanotransduction pathways. Because Ca regulates a vast range of downstream cellular processes, a better understanding of how ultrasound influences Ca signaling could lead to new applications for ultrasound. In this study, we investigated the mechanism of ultrasound-induced Ca mobilization in human mesenchymal stem cells using 47 MHz focused ultrasound to stimulate single cells at low intensities (~ 110 mW/cm). 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 PY purinergic receptors on the membrane, in turn activating phospholipase C, which evokes production of inositol trisphosphate and release of Ca from intracellular stores.

Janus 3D printed dynamic scaffolds for nanodeflection-driven bone regeneration

“…ATP release has also been shown to increase upon direct low-intensity ultrasound stimulation, and consequent depolarization of the cell membrane, during osteogenic differentiation of MC3T3-E1 cells and in 2D cultures of mesenchymal stem cells, which is in agreement with what we observed here (Fig. 4e) 33,34 .…”

Intermittent pulsed electromagnetic field stimulation activates the mTOR pathway and stimulates the proliferation of osteoblast‐like cells

“…Physical stimulation is one of the bone fusion‐promoting treatments, in which bone fusion‐promoting devices using low‐intensity pulsed ultrasound (LIPUS) and pulsed electromagnetic fields (PEMFs) have been clinically applied. LIPUS waves cause nanomotion at the fractured site, and one of the mechanisms for enhancing fracture repair is by inducing cyclooxygenase 2 (COX‐2) [Harrison et al, ] and stimulating the release of calcium ion from the intracellular stores [Yoon et al, ].…”

Investigation of Ultrasound-Mediated Intracellular Ca2+ Oscillations in HIT-T15 Pancreatic β-Cell Line

“…To test whether ultrasound stimulation can also evoke intracellular Ca 2+ oscillations from resting cells as shown in the high-glucose stimulation, a cluster of HIT-T15 cells was exposed to 45-MHz pulsed ultrasound. In this study, the power (I SPTA ) of the ultrasound was fixed at 113.1 mW/cm 2 (input voltage: 60 mV, pulse repetition time: 1 ms, duty factor: 2%) to be in the range of low-intensity and also comparable to our previous reports [16,18]. The ultrasound stimulation setup is illustrated in Figure 1a.…”

“…In the pancreatic β-cells, ATP is released either from nerve terminals [27,28] or secretory granules [29], and it plays several physiological roles [30]. We hypothesized that ultrasound induces the oscillatory Ca 2+ responses by facilitating ATP release via mechanosensitive hemichannels based on our previous study [18].…”

“…For the last few years, our group has reported that focused ultrasound can induce intracellular Ca 2+ elevations in cancer cell lines [15,16], human umbilical vein endothelial cells (HUVECs) [17], and human mesenchymal stem cells (hMSCs) [18]. In the recent report, we suggested the concept of an ultrasound-based intracellular Ca 2+ signaling modulator, which possesses the capability to regulate downstream Ca 2+ -dependent cellular processes non-invasively and remotely.…”