Adhesive Force Regulation and Mechanotransduction

Integrin-mediated adhesion to extracellular matrices provides forces and signals that direct cell processes central to tissue organization, homeostasis, repair, and disease. Focal adhesions (FAs) are nano/micron-scale complexes of clustered integrins and structural and signaling molecules that link the matrix to the cytoskeleton and function as principal sites of force transmission and signal transduction. Despite significant progress in defining biochemical interactions driving FA assembly and signaling, very little is known about how FAs sense and transmit force and how these forces are integrated into biochemical signals. Dr. García has integrated force-sensing platforms, photoactivatable adhesive ligands, and nano/micropatterned substrates as well as unique cell lines expressing FA mutants to analyze the regulation of adhesive forces and mechanotransduction. This research has provided unique findings about adhesive force regulation that cannot be obtained using conventional assays. Using these bioengineering platforms, Dr. García discovered that human pluripotent stem cells exhibit a unique ‘adhesive force signature’ from parental cells and differentiated progeny and established a novel strategy to rapidly and efficiently purify human stem cells and progeny based on differences in adhesive force. Dr. García established a synthetic ECM-mimetic hydrogel platform with independent control over adhesive ligand density, mechanical properties, and proteolytic degradation to study epithelial morphogenesis. This technology provides a valuable tool to study how cells transduce ECM properties into morphogenetic behaviors.

  1. Coyer SR, Singh A, Dumbauld DW, Calderwood DA, Craig SW, Delamarche E, García AJ. Nanopatterning reveals an ECM area threshold for focal adhesion assembly and force transmission that is regulated by integrin activation and cytoskeleton tension. J Cell Sci 2012; 125: 5110-23. PMC3533393.
  2. Singh A, Suri S, Lee T, Chilton JM, Cooke MT, Chen W, Fu J, Stice SL, Lu H, McDevitt TC, García AJ. Adhesion strength-based, label-free isolation of human pluripotent stem cells. Nat Methods 2013; 10:438-44. PMC3641175.
  3. Dumbauld DW, Lee TT, Singh A, Scrimgeour J, Gersbach CA, Zamir EA, Fu J, Chen CS, Curtis JE, Craig SW, García AJ. How vinculin regulates force transmission. Proc Natl Acad Sci USA 2013; 110:9788-93. PMC3683711.
  4. Enemchukwu NO, Cruz-Acuña R, Bongiorno T, Johnson CT, García JR, Sulchek T, García AJ. Synthetic matrices reveal contributions of ECM biophysical and biochemical properties to epithelial morphogenesis. J Cell Biol 2016; 212:113-24. PMC4700478.