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Article 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 integrin engagement in particular has been correlated with fibroblast activation into contractile myofibroblasts that drive fibrosis progression. There is a significant unmet need for 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 3 or 51.
Results: On fibrosis-mimicking stiff elastic hydrogels, preferential 3 engagement promoted increased spreading, actin stress fiber organization, and focal adhesion maturation as indicated by paxillin organization in human lung fibroblasts. In contrast, preferential 51 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.
Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-021-00672-1.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548477 | PMC |
| http://dx.doi.org/10.1007/s12195-021-00672-1 | DOI Listing |
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