Dynamics and mechanisms of intracellular calcium waves elicited by tandem bubble-induced jetting flow

Author:

Li FenfangORCID,Yang Chen,Yuan Fang,Liao Defei,Li Thomas,Guilak FarshidORCID,Zhong Pei

Abstract

One of the earliest events in cellular mechanotransduction is often an increase in intracellular calcium concentration associated with intracellular calcium waves (ICWs) in various physiologic or pathophysiologic processes. Although cavitation-induced calcium responses are believed to be important for modulating downstream bioeffects such as cell injury and mechanotransduction in ultrasound therapy, the fundamental mechanisms of these responses have not been elucidated. In this study, we investigated mechanistically the ICWs elicited in single HeLa cells by the tandem bubble-induced jetting flow in a microfluidic system. We identified two distinct (fast and slow) types of ICWs at varying degrees of flow shear stress-induced membrane deformation, as determined by different bubble standoff distances. We showed that ICWs were initiated by an extracellular calcium influx across the cell membrane nearest to the jetting flow, either primarily through poration sites for fast ICWs or opening of mechanosensitive ion channels for slow ICWs, which then propagated in the cytosol via a reaction−diffusion process from the endoplasmic reticulum. The speed of ICW (CICW) was found to correlate strongly with the severity of cell injury, with CICW in the range of 33 μm/s to 93 μm/s for fast ICWs and 1.4 μm/s to 12 μm/s for slow ICWs. Finally, we demonstrated that micrometer-sized beads attached to the cell membrane integrin could trigger ICWs under mild cavitation conditions without collateral injury. The relation between the characteristics of ICW and cell injury, and potential strategies to mitigate cavitation-induced injury while evoking an intracellular calcium response, may be particularly useful for exploiting ultrasound-stimulated mechanotransduction applications in the future.

Funder

HHS | NIH | National Institute of Biomedical Imaging and Bioengineering

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases

NSF | ENG | Division of Civil, Mechanical and Manufacturing Innovation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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