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The Combined Influence of Viscoelastic and Adhesive Cues on Fibroblast Spreading and Focal Adhesion Organization

  • 2021 CMBE Young Innovators
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Abstract

Introduction

Tissue fibrosis is characterized by progressive extracellular matrix (ECM) stiffening and loss of viscoelasticity that ultimately impairs organ functionality. Cells bind to the ECM through integrins, where αv integrin engagement in particular has been correlated with fibroblast activation into contractile myofibroblasts that drive fibrosis progression. There is a significant unmet need for in vitro hydrogel systems that deconstruct the complexity of native tissues to better understand the individual and combined effects of stiffness, viscoelasticity, and integrin engagement on fibroblast behavior.

Methods

We developed hyaluronic acid hydrogels with independently tunable cell-instructive properties (stiffness, viscoelasticity, ligand presentation) to address this challenge. Hydrogels with mechanics matching normal or fibrotic lung tissue were synthesized using a combination of covalent crosslinks and supramolecular interactions to tune viscoelasticity. Cell adhesion was mediated through incorporation of either RGD peptide or engineered fibronectin fragments promoting preferential integrin engagement via αvβ3 or α5β1.

Results

On fibrosis-mimicking stiff elastic hydrogels, preferential αvβ3 engagement promoted increased spreading, actin stress fiber organization, and focal adhesion maturation as indicated by paxillin organization in human lung fibroblasts. In contrast, preferential α5β1 binding suppressed these metrics. Viscoelasticity, mimicking the mechanics of healthy tissue, largely curtailed fibroblast spreading and focal adhesion organization independent of adhesive ligand type, highlighting its role in reducing fibroblast-activating behaviors.

Conclusions

Together, these results provide new insights into how mechanical and adhesive cues collectively guide disease-relevant cell behaviors.

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Acknowledgments

This work was supported by the UVA Fibrosis Initiative and the NIH (R35GM138187, T32GM008715). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Chemical Engineering, University of Virginia, 102 Engineer’s Way, Charlottesville, VA, 22904, USA

    Erica Hui & Steven R. Caliari

  2. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22904, USA

    Leandro Moretti, Thomas H. Barker & Steven R. Caliari

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Steven R. Caliari joined the faculty of the University of Virginia in fall 2016 as an Assistant Professor in the Department of Chemical Engineering with a secondary appointment in the Department of Biomedical Engineering. Prior to joining UVA he was an NIH Postdoctoral Fellow in the Department of Bioengineering at the University of Pennsylvania. Steven completed his B.S. in Chemical Engineering at the University of Florida and received both his M.S. and Ph.D. in Chemical Engineering from the University of Illinois at Urbana-Champaign. His lab designs biomaterials to study the dynamic reciprocity between cells and their microenvironment, applying these platforms to address fundamental human health challenges in understanding disease and engineering tissues. Steven recently received the NIH (NIGMS) Maximizing Investigators’ Research Award (MIRA) and NSF CAREER Award. His lab is grateful for generous support from the NIH, DoD, NSF, V Foundation, and UVA-Coulter Translational Research Partnership. To learn more about the lab’s work, please follow @Caliari_Lab on Twitter.

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This article is part of the 2021 CMBE Young Innovators special issue.

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Supplementary material 1 1H NMR spectra for NorHA and CD-HA, MALDI spectra for the adamantane peptide, additional hydrogel mechanical characterization, and additional cell analysis can be found in the Supporting Information. (PDF 1197 kb)

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Hui, E., Moretti, L., Barker, T.H. et al. The Combined Influence of Viscoelastic and Adhesive Cues on Fibroblast Spreading and Focal Adhesion Organization. Cel. Mol. Bioeng. 14, 427–440 (2021). https://doi.org/10.1007/s12195-021-00672-1

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