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The combined influence of viscoelasticity and adhesive cues on fibroblast spreading and focal adhesion formation

View ORCID ProfileErica Hui, Leandro Moretti, Thomas H. Barker, View ORCID ProfileSteven R. Caliari
doi: https://doi.org/10.1101/2021.02.17.430924
Erica Hui
aDepartment of Chemical Engineering, University of Virginia, Charlottesville, Virginia 22904
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Leandro Moretti
bDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904
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Thomas H. Barker
bDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904
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Steven R. Caliari
aDepartment of Chemical Engineering, University of Virginia, Charlottesville, Virginia 22904
bDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904
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  • ORCID record for Steven R. Caliari
  • For correspondence: caliari@virginia.edu
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Abstract

Tissue fibrosis is characterized by progressive extracellular matrix (ECM) stiffening and loss of viscoelasticity that ultimately results in reduced organ functionality. Cells bind to the ECM through integrins, where av 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. Here, 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. We showed that preferential αvβ3 engagement enabled human lung fibroblasts to assume a myofibroblast-like phenotype on fibrosis-mimicking stiff elastic hydrogels with increased spreading, actin stress fiber organization, and focal adhesion maturation as indicated by paxillin organization. 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 preventing fibroblast activation. Together these results provide new insights into how mechanical and adhesive cues collectively guide disease-relevant cell behaviors.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 17, 2021.
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The combined influence of viscoelasticity and adhesive cues on fibroblast spreading and focal adhesion formation
Erica Hui, Leandro Moretti, Thomas H. Barker, Steven R. Caliari
bioRxiv 2021.02.17.430924; doi: https://doi.org/10.1101/2021.02.17.430924
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The combined influence of viscoelasticity and adhesive cues on fibroblast spreading and focal adhesion formation
Erica Hui, Leandro Moretti, Thomas H. Barker, Steven R. Caliari
bioRxiv 2021.02.17.430924; doi: https://doi.org/10.1101/2021.02.17.430924

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