Smooth Muscle Stiffness Sensitivity is Driven by Soluble and Insoluble ECM ChemistryCellular and Molecular Bioengineering
AbstractSmooth muscle cell (SMC) invasion into plaques and subsequent proliferation is a major factor in the progression of atherosclerosis. During disease progression, SMCs experience major changes in their microenvironment, such as what integrin-binding sites are exposed, the portfolio of soluble factors available, and the elasticity and modulus of the surrounding vessel wall. We have developed a hydrogel biomaterial platform to examine the combined effect of these changes on SMC phenotype. We were particularly interested in how the chemical microenvironment affected the ability of SMCs to sense and respond to modulus. To our surprise, we observed that integrin binding and soluble factors are major drivers of several critical SMC behaviors, such as motility, proliferation, invasion, and differentiation marker expres- sion, and these factors modulated the effect of stiffness on proliferation and migration. Overall, modulus only modestly affected behaviors other than proliferation, relative to integrin binding and soluble factors. Surprisingly, patho- logical behaviors (proliferation, motility) are not inversely related to SMC marker expression, in direct conﬂict with previous studies on substrates coupled with single extracel- lular matrix (ECM) proteins. A high-throughput bead-based ELISA approach and inhibitor studies revealed that differ- entiation marker expression is mediated chieﬂy via focal adhesion kinase (FAK) signaling, and we propose that integrin binding and FAK drive the transition from a migratory to a proliferative phenotype. We emphasize the importance of increasing the complexity of in vitro testing platforms to capture these subtleties in cell phenotypes and signaling, in order to better recapitulate important features of in vivo disease and elucidate potential context-dependent therapeutic targets.
FunderThis work was supported by a Grant in Aid from the American Heart Association (13GRNT16190013), a Barry and Afsaneh Siadat Career Development Award, grants from the National Science Foundation and the National Cancer Institute (DMR-1234852 and DMR-1304724), start-up funds from the University of Massachusetts Amherst, and the UMass MRSEC on Polymers (DMR-0820506). WGH was supported by a fellowship from the Institute of Cellular Engineering IGERT at UMass (DGE-0654128). SRP is a Pew Biomedical Scholar supported by the Pew Charitable Trusts.
Citation InformationWilliam G Herrick, Shruti Rattan, Thuy V. Nguyen, Michael S. Grunwald, et al.. "Smooth Muscle Stiffness Sensitivity is Driven by Soluble and Insoluble ECM Chemistry" Cellular and Molecular Bioengineering Vol. 8 Iss. 3 (2015)
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