title: Reprogramming cardiomyocyte mechanosensing by crosstalk between integrins and hyaluronic acid receptors.
abstract: The elastic modulus of bioengineered materials has a strong influence on the phenotype of many cells including cardiomyocytes. On polyacrylamide (PAA) gels that are laminated with ligands for integrins, cardiac myocytes develop well organized sarcomeres only when cultured on substrates with elastic moduli in the range 10 kPa-30 kPa, near those of the healthy tissue. On stiffer substrates (>60 kPa) approximating the damaged heart, myocytes form stress fiber-like filament bundles but lack organized sarcomeres or an elongated shape. On soft (<1 kPa) PAA gels myocytes exhibit disorganized actin networks and sarcomeres. However, when the polyacrylamide matrix is replaced by hyaluronic acid (HA) as the gel network to which integrin ligands are attached, robust development of functional neonatal rat ventricular myocytes occurs on gels with elastic moduli of 200 Pa, a stiffness far below that of the neonatal heart and on which myocytes would be amorphous and dysfunctional when cultured on polyacrylamide-based gels. The HA matrix by itself is not adhesive for myocytes, and the myocyte phenotype depends on the type of integrin ligand that is incorporated within the HA gel, with fibronectin, gelatin, or fibrinogen being more effective than collagen I. These results show that HA alters the integrin-dependent stiffness response of cells in vitro and suggests that expression of HA within the extracellular matrix (ECM) in vivo might similarly alter the response of cells that bind the ECM through integrins. The integration of HA with integrin-specific ECM signaling proteins provides a rationale for engineering a new class of soft hybrid hydrogels that can be used in therapeutic strategies to reverse the remodeling of the injured myocardium.
authors.affiliation: Department of Biomedical Engineering, Drexel University, Philadelphia, PA 19102, USA.
authors.forename: Anant
authors.initials: A
authors.lastname: Chopra
authors.forename: Victor
authors.initials: V
authors.lastname: Lin
authors.forename: Amanda
authors.initials: A
authors.lastname: McCollough
authors.forename: Sarah
authors.initials: S
authors.lastname: Atzet
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Wechsler
authors.forename: Maria E
authors.initials: ME
authors.lastname: Murray
authors.forename: Shaina A
authors.initials: SA
authors.lastname: Oake
authors.forename: J Yasha
authors.initials: JY
authors.lastname: Kresh
authors.forename: Paul A
authors.initials: PA
authors.lastname: Janmey
mesh_terms: D000180:Acrylic Resins / Q000378:metabolism; D000199:Actins / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001672:Biocompatible Materials / Q000378:metabolism*; D057005:Bioengineering / Q000379:methods; D001696:Biomechanical Phenomena / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods; D024042:Collagen Type I / Q000378:metabolism; D055119:Elastic Modulus / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D005780:Gelatin / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism*; D020100:Hydrogels / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk; D012518:Sarcomeres / Q000378:metabolism / Q000502:physiology; D023822:Tissue Engineering / Q000379:methods
chemical_list: D000180:Acrylic Resins; D000199:Actins; D001672:Biocompatible Materials; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D020100:Hydrogels; D016023:Integrins; C016680:polyacrylamide gels; D005780:Gelatin; D005340:Fibrinogen; D006820:Hyaluronic Acid