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Cellular Mechanotransduction

 

Many of the clinical symptoms that cause patients to visit the doctor’s office result from changes in tissue structure or altered mechanics. In fact, a wide range of diseases included within virtually all fields of medicine and surgery share a common feature: their etiology and clinical presentation result from abnormal cell and tissue responses to mechanical stress. Yet, little is known about the process of mechanotransduction – how cells sense mechanical signals and convert them into a biochemical response. Our work has demonstrated that cells sense mechanical stresses through changes in the balance of forces that are transmitted across transmembrane integrin receptors that link the ECM to the cytoskeleton.

We have developed micromagnetic and nanomagnetic technologies to apply controlled mechanical stresses to specific cell surface receptors via surface-bound, ligand-coated, magnetic micro- and nano-beads. Using these methods, we have been able to show that cells respond differently when stresses are applied to adhesion receptors, such as integrins, that mechanically couple to the cytoskeleton than when they are exerted on other transmembrane receptors (e.g., metabolic receptors, HLA antigen). For example, twisting of integrin-bound magnetic microbeads activates signal transduction cascades that influence gene transcription (e.g., involving heterotrimeric G proteins, adenylyl cyclase and the downstream cAMP pathway), whereas twisting of beads bound to other transmembrane receptors has no effect. Furthermore, our studies have shown that integrins must be in an "activated" state that promotes formation of intact focal adhesions which physically link to the cytoskeleton in order for the mechanical signal to be effectively transduced into a chemical response. One area of current focus is analysis of the molecular basis of this form of integrin-dependent mechanotransduction across the cell surface.

 

 

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