title: Myofibroblastic activation of valvular interstitial cells is modulated by spatial variations in matrix elasticity and its organization.
abstract: Valvular interstitial cells (VICs) are key regulators of the heart valve's extracellular matrix (ECM), and upon tissue damage, quiescent VIC fibroblasts become activated to myofibroblasts. As the behavior of VICs during disease progression and wound healing is different compared to healthy tissue, we hypothesized that the organization of the matrix mechanics, which results from depositing of collagen fibers, would affect VIC phenotypic transition. Specifically, we investigated how the subcellular organization of ECM mechanical properties affects subcellular localization of Yes-associated protein (YAP), an early marker of mechanotransduction, and α-smooth muscle actin (α-SMA), a myofibroblast marker, in VICs. Photo-tunable hydrogels were used to generate substrates with different moduli and to create organized and disorganized patterns of varying elastic moduli. When porcine VICs were cultured on these matrices, YAP and α-SMA activation were significantly increased on substrates with higher elastic modulus or a higher percentage of stiff regions. Moreover, VICs cultured on substrates with a spatially disorganized elasticity had smaller focal adhesions, less nuclear localized YAP, less α-SMA organization into stress fibers and higher proliferation compared to those cultured on substrates with a regular mechanical organization. Collectively, these results suggest that disorganized spatial variations in mechanics that appear during wound healing and fibrotic disease progression may influence the maintenance of the VIC fibroblast phenotype, causing more proliferation, ECM remodeling and matrix deposition.
authors.affiliation: Department of Chemical and Biological Engineering, University of Colorado at Boulder, Boulder, CO 80309, USA; BioFrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Ma
authors.affiliation: BioFrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309, USA; Department of Materials Science and Engineering, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Anouk R
authors.initials: AR
authors.lastname: Killaars
authors.affiliation: Material Measurement Laboratory, National Institute of Standards and Technology, Boulder, CO 80305, USA.
authors.forename: Frank W
authors.initials: FW
authors.lastname: DelRio
authors.affiliation: BioFrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309, USA; Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Chemical and Biological Engineering, University of Colorado at Boulder, Boulder, CO 80309, USA; BioFrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309, USA; Howard Hughes Medical Institute, University of Colorado at Boulder, Boulder, CO 80309, USA. Electronic address: kristi.anseth@colorado.edu.
authors.forename: Kristi S
authors.initials: KS
authors.lastname: Anseth
mesh_terms: D000199:Actins / Q000032:analysis / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001672:Biocompatible Materials / Q000378:metabolism; D001696:Biomechanical Phenomena; D049109:Cell Proliferation; D002478:Cells, Cultured; D055119:Elastic Modulus; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006351:Heart Valves / Q000166:cytology* / Q000378:metabolism; D020100:Hydrogels / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000378:metabolism; D013552:Swine
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D001672:Biocompatible Materials; D020100:Hydrogels; D011092:Polyethylene Glycols
keywords: Hydrogels; Matrix elasticity; Photopatterning; Valvular interstitial cell (VIC); Yes-associated protein (YAP); α-smooth muscle actin (α-SMA)