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Smooth Muscle Stiffness Sensitivity is Driven by Soluble and Insoluble ECM Chemistry

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Abstract

Smooth 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 expression, 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, pathological behaviors (proliferation, motility) are not inversely related to SMC marker expression, in direct conflict with previous studies on substrates coupled with single extracellular matrix (ECM) proteins. A high-throughput bead-based ELISA approach and inhibitor studies revealed that differentiation 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.

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Acknowledgements

This 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. We are also grateful to Dr. Nele Van Dessel for helpful discussions.

Conflict of interests

William G. Herrick, Shruti Rattan, Thuy V. Nguyen, Michael S. Grunwald, Christopher W. Barney, Alfred J. Crosby, and Shelly R. Peyton declare no conflicts of interest. No human studies were carried out by the authors for this article. No animal studies were carried out by the authors for this article.

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Authors and Affiliations

  1. Department of Chemical Engineering, University of Massachusetts, 686 N. Pleasant Street, 159 Goessmann Laboratory, Amherst, MA, 01003, USA

    William G. Herrick, Thuy V. Nguyen, Michael S. Grunwald & Shelly R. Peyton

  2. Polymer Science and Engineering Department, University of Massachusetts, Conte Polymer Research Center, 120 Governors Dr., Amherst, MA, 01003, USA

    Shruti Rattan & Alfred J. Crosby

  3. Department of Materials Engineering, Purdue University, West Lafayette, USA

    Christopher W. Barney

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  1. William G. Herrick
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Correspondence to Shelly R. Peyton.

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Associate Editor Cynthia A. Reinhart-King oversaw the review of this article.

This article is part of the 2015 Young Innovators Issue.

Shelly R. Peyton is the Barry and Afsaneh Siadat Assistant Professor of Chemical Engineering at the University of Massachusetts, Amherst. She received her B.S. in Chemical Engineering from Northwestern University in 2002 and went on to obtain her MS and Ph.D. in Chemical Engineering from the University of California, Irvine. She was then an NIH Kirschstein post-doctoral fellow in the Biological Engineering department at MIT before starting her academic appointment at UMass in 2011. Her research interests are in biomaterial design and understanding how cell-material interactions contribute to cancer aggressiveness, cardiovascular disease progression, and regenerative medicine. Since arriving at UMass she has been named a Pew Biomedical Scholar, received a New Innovator Award from the NIH, and she was recently awarded a CAREER grant from the NSF.

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Herrick, W.G., Rattan, S., Nguyen, T.V. et al. Smooth Muscle Stiffness Sensitivity is Driven by Soluble and Insoluble ECM Chemistry. Cel. Mol. Bioeng. 8, 333–348 (2015). https://doi.org/10.1007/s12195-015-0397-4

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