Sonoepigenetics: Spatiotemporal Calcium Dynamics and cAMP Signaling Driven by High Frequency Nanomechanostimulation Regulates Transient Epigenetic Modifications and Early Osteogenic Commitment in Mesenchymal Stem Cells

Abstract

Cells effectively balance and integrate numerous pathways to adapt to external signals in an attempt to regain homeostasis, although the complex nuclear mechanotransduction mechanism through which this occurs is not as yet fully understood. Contrary to prevalent thought that the relay of extracellular cues to the nucleus to effect its fate and function predominantly relies on direct transmission through the cytoskeletal structure, we demonstrate, through the use of high frequency (10 MHz) nanomechanostimulation, that induced fluctuations of the cells nuclear chromatin response are primarily influenced by the spatiotemporal dynamics associated with the bidirectional crosstalk between two key second messengers, namely calcium (Ca2+) and cyclic adenosine monophosphate (cAMP). We show that this conditioning is an adaptive response to the mechanostimuli and correlates with a mechanopriming effect. Notably, brief (10 mins) daily exposure to the mechanostimulation was sufficient to direct mesenchymal stem cells toward an osteogenic lineage in as little as three days--without the need for osteogenic factors.