Figure 9.

Schematic of intracellular Ca²⁺ signaling that generates ultrasound bioeffects for enhanced MSC homing. This study demonstrates that 1) pFUS mechanically activates cationic TRPC1 channels that conduct depolarizing currents and 2) activate nearby VCGG to amplify cytosolic Ca²⁺ concentrations. Other potential but uninvestigated downstream mediators of cytosolic Ca²⁺ influx could be 3) Ca²⁺-induced Ca²⁺-release (CICR) through ryanodine receptors (RyR) following VGCC activation and 4) the TRPC1/ORAI1/STIM1 complex, which may be involved in downstream store operated Ca²⁺ entry (SOCE) following potential ER/SR depletion. 5) The ultimate effect of increased cytosolic Ca²⁺ is activation of nuclear factor κ B (NFκB) which generates molecular responses (including COX2) necessary to generate the variety of cytokines, chemokines, trophic factors, and cell adhesion molecules that are necessary to induce tropism of infused MSC ¹⁶.