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

Cells effectively balance and integrate numerous pathways to adapt to external signals in an attempt to regain homeostasis, although the complex nuclear mechan-otransduction 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 a unique form of high frequency (10 MHz) nanomechanostimulation, that manipulations to the cells’ nuclear chromatin response are primarily influenced by the spatiotemporal dynamics associated with the bidirectional crosstalk between two key second messengers, namely calcium (Ca ²⁺ ) and cyclic adenosine monophosphate (cAMP). In stem cells, we show this conditioning, as an adaptive response to the mechanostimuli, to correlate with a ‘mechanopriming’ effect that is responsible for their early induction towards an osteogenic lineage in as little as three days with just brief (10 mins) daily bursts of mechanostimulation, without the need for osteogenic factors.