Mechanotransduction

Abstract

Physical forces are central players in development and morphogenesis, provide an ever-present backdrop influencing physiological functions, and contribute to a variety of pathologies. Mechanotransduction encompasses the rich variety of ways in which cells and tissues convert cues from their physical environment into biochemical signals. These cues include tensile, compressive and shear stresses, and the stiffness or elastic modulus of the tissues in which cells reside. This article focuses on the proximal events that lead directly from a change in physical state to a change in cell-signaling state. A large body of evidence demonstrates a prominent role for the extracellular matrix, the intracellular cytoskeleton, and the cell matrix adhesions that link these networks in transduction of the mechanical environment. Recent work emphasizes the important role of physical unfolding or conformational changes in proteins induced by mechanical loading, with examples identified both within the focal adhesion complex at the cell-matrix interface and in extracellular matrix proteins themselves. Beyond these adhesion and matrix-based mechanisms, classical and new mechanisms of mechanotransduction reside in stretch-activated ion channels, the coupling of physical forces to interstitial autocrine and paracrine signaling, force-induced activation of extracellular proteins, and physical effects directly transmitted to the cell's nucleus. Rapid progress is leading to detailed delineation of molecular mechanisms by which the physical environment shapes cellular signaling events, opening up avenues for exploring how mechanotransduction pathways are integrated into physiological and pathophysiological cellular and tissue processes.

Mechanobiological Feedback in Pulmonary Vascular Disease

“…The transmission of mechanical information from the ECM to the cell cytoskeleton and signal transduction machinery is mediated primarily through integrin-based adhesions ( Tschumperlin, 2011 ; Tschumperlin et al, 2018 ). Integrins, comprising heterodimers of α and β subunits, are transmembrane proteins that recognize specific matrix polypeptides, such as the arginine-glycine-aspartic acid (RGD) sequence in fibronectin.…”

“…Downstream of cell-matrix and cell-cell adhesion molecules, a large network of biochemical and cytoskeletal-interacting pathways contribute to the transduction of mechanical signals, however, a few key molecules have emerged as critical ( Figure 2 ). For instance, the Src family of tyrosine kinases and FAK are both recruited to focal adhesions, modulate integrin-cytoskeletal links, and regulate each other’s activity ( Tschumperlin, 2011 ; Bloodworth et al, 2015 ). In particular, Src activity has been shown to increase FAK expression at the cell surface and lead to greater force transmission in vascular smooth muscle; conversely, inhibition of FAK decreases Src activity in PASMCs ( Paulin et al, 2014 ; Bloodworth et al, 2015 ).…”

Synthesis and Different Effects of Biotinylated PAMAM G3 Dendrimer Substituted with Nimesulide in Human Normal Fibroblasts and Squamous Carcinoma Cells

“…At higher concentration of the conjugates, the inhibitory effect may appear. Currently, a new concept of cell fate regulation including interaction with adhesion and extracellular matrix-based mechanisms and new mechanisms of mechanotransduction has been proposed that may explain this experimental data [78,79].…”

Limitations of recellularized biological scaffolds for human transplantation

“…One of the major advantages of acellular natural scaffolds is that they should retain the native ECM composition, topography, and biomechanics that is known to be organ specific (Petersen et al, 2010;Shojaie et al, 2015;Tschumperlin, 2015;Weber, Annenberg, Wright, Braverman, & Mesh, 2014;Zhou et al, 2018). ECM is essential for cell attachment, proliferation, differentiation, and therefore, regeneration (Lawson et al, 2016;Mih, Marinkovic, Liu, Sharif, & Tschumperlin, 2012;Petersen et al, 2010;Susek et al, 2018).…”