Cellular Mechanotransduction: From Tension to Function

Abstract

Living cells are constantly exposed to mechanical stimuli arising from the surrounding extracellular matrix (ECM) or from neighboring cells. The intracellular molecular processes through which such physical cues are transformed into a biological response are collectively dubbed as mechanotransduction and are of fundamental importance to help the cell timely adapt to the continuous dynamic modifications of the microenvironment. Local changes in ECM composition and mechanics are driven by a feed forward interplay between the cell and the matrix itself, with the first depositing ECM proteins that in turn will impact on the surrounding cells. As such, these changes occur regularly during tissue development and are a hallmark of the pathologies of aging. Only lately, though, the importance of mechanical cues in controlling cell function (e.g., proliferation, differentiation, migration) has been acknowledged. Here we provide a critical review of the recent insights into the molecular basis of cellular mechanotransduction, by analyzing how mechanical stimuli get transformed into a given biological response through the activation of a peculiar genetic program. Specifically, by recapitulating the processes involved in the interpretation of ECM remodeling by Focal Adhesions at cell-matrix interphase, we revise the role of cytoskeleton tension as the second messenger of the mechanotransduction process and the action of mechano-responsive shuttling proteins converging on stage and cell-specific transcription factors. Finally, we give few paradigmatic examples highlighting the emerging role of malfunctions in cell mechanosensing apparatus in the onset and progression of pathologies.

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“…Among the mechanisms responsible for regulating cellular growth and homeostasis in a dynamic cellular environment, behaviors such as cell–cell interaction, cell–substrate interaction, and cell migration are emerging as key players . Given their dynamic and multifaceted role, mechanical signals responsible for coordinating cell behaviors appear at the interface between environmental cues and the control of epigenetic memory . Figure 2 shows a possible mechanism to explain how behavioral responses to environment alterations or mechanical stimulation under different culture conditions induce cell‐to‐cell variability.…”

“…Figure 2 shows a possible mechanism to explain how behavioral responses to environment alterations or mechanical stimulation under different culture conditions induce cell‐to‐cell variability. Cells respond to mechanical signals in the form of externally applied force and of forces generated by cell–substrate and cell–cell interactions during migration . When mechanical stimuli are applied to the extracellular domain of integrins present on the plasma membrane, mechanical stress from the extracellular matrix (ECM) can be transmitted into the nucleus, inducing significant alterations in nuclear morphology and stiffness .…”

“…Cells respond to mechanical signals in the form of externally applied force and of forces generated by cell–substrate and cell–cell interactions during migration . When mechanical stimuli are applied to the extracellular domain of integrins present on the plasma membrane, mechanical stress from the extracellular matrix (ECM) can be transmitted into the nucleus, inducing significant alterations in nuclear morphology and stiffness . The ability of the cell to sense and respond to their environmental mechanical stimulus by translating a mechanical cue into intracellular biochemical signaling is known as mechanotransduction .…”

“…Recently, it has been found that altered cytoskeletal organization in response to changes in intracellular tension is associated with changes in the levels of histone acetylation, and mechanical stress has been linked to an increase in histone H3 and H4 acetylation, thereby resulting in a transcriptionally active chromatin architecture . The mechanical stress‐induced epigenetic changes thus suggest a mechanism by which mechanical stress alters histone acetylation . The sequestering of histone deacetylases through actin filaments indicates that the actin cytoskeleton can directly influence gene expression by regulating the nuclear‐cytoplasmic shuttling of epigenetic regulators …”

“…Because hPSCs can divide without limit, this phenomenon may become predominant over time, creating a functionally heterogeneous cell population. Changes in mechanical forces within colonies or aggregates can result in misregulation of intracellular signaling pathways and lead to cell variability …”