title: Myocardial contraction and hyaluronic acid mechanotransduction in epithelial-to-mesenchymal transformation of endocardial cells.
abstract: Epithelial-to-mesenchymal transition (EMT) of endocardial cells is a critical initial step in the formation of heart valves. The collagen gel in vitro model has provided significant information on the role of growth factors regulating EMT but has not permitted investigation of mechanical factors. Therefore we sought to develop a system to probe the effects of mechanical inputs on endocardial EMT by incorporating hyaluronic acid (HA), the primary component of endocardial cushions in developing heart valves, into the gel assay. This was achieved using a combination collagen and crosslinkable methacrylated HA hydrogel (Coll-MeHA). Avian atrioventricular canal explants on Coll-MeHA gels showed increased numbers of transformed cells. Analysis of the mechanical properties of Coll-MeHA gels shows that stiffness does not directly affect EMT. Hydrogel deformation from the beating myocardium of explants directly led to higher levels of regional gel deformation and larger average strain magnitudes associated with invaded cells on Coll-MeHA gels. Inhibition of this contraction reduced EMT on all gel types, although to a lesser extent on Coll-MeHA gels. Using the system we have developed, which permits the manipulation of mechanical factors, we have demonstrated that active mechanical forces play a role in the regulation of endocardial EMT.
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Mary Kathryn
authors.initials: MK
authors.lastname: Sewell-Loftin
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: DeLaughter
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Jon R
authors.initials: JR
authors.lastname: Peacock
authors.affiliation: Department of Pediatrics, Division of Cardiology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Brown
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Pediatrics, Division of Cardiology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: H Scott
authors.initials: HS
authors.lastname: Baldwin
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Joey V
authors.initials: JV
authors.lastname: Barnett
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: david.merryman@vanderbilt.edu.
authors.forename: W David
authors.initials: WD
authors.lastname: Merryman
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D024042:Collagen Type I / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004699:Endocardium / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D040542:Mechanotransduction, Cellular / Q000187:drug effects*; D008689:Methacrylates / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D054457:Tissue Scaffolds / Q000737:chemistry
chemical_list: D024042:Collagen Type I; D003432:Cross-Linking Reagents; D008689:Methacrylates; D006820:Hyaluronic Acid
keywords: Collagen; Epithelial-to-mesenchymal transition (EMT); Heart valve; Hyaluronic acid; Mechanical properties