title: Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation.
abstract: Integrin-mediated force application induces a conformational change in latent TGF-β1 that leads to the release of the active form of the growth factor from the extracellular matrix (ECM). Mechanical activation of TGF-β1 is currently understood as an acute process that depends on the contractile force of cells. However, we show that ECM remodeling, preceding the activation step, mechanically primes latent TGF-β1 akin to loading a mechanical spring. Cell-based assays and unique strain devices were used to produce a cell-derived ECM of controlled organization and prestrain. Mechanically conditioned ECM served as a substrate to measure the efficacy of TGF-β1 activation after cell contraction or direct force application using magnetic microbeads. The release of active TGF-β1 was always higher from prestrained ECM as compared with unorganized and/or relaxed ECM. The finding that ECM prestrain regulates the bioavailability of TGF-β1 is important to understand the context of diseases that involve excessive ECM remodeling, such as fibrosis or cancer.
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Franco
authors.initials: F
authors.lastname: Klingberg
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Chow
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Koehler
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Stellar
authors.initials: S
authors.lastname: Boo
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Lara
authors.initials: L
authors.lastname: Buscemi
authors.affiliation: Soft Tissue Biophysics Laboratory, Department of Chemical Engineering, McGill University, Montreal, Quebec H3A 2B2, Canada.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Quinn
authors.affiliation: Laboratory of Extracellular Matrix Proteins, Department of Biochemistry and Molecular Biology, Faculty of Biology, University of València, 46100 València, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Costell
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
authors.affiliation: Centre Cardiothoracique de Bordeaux, U1045, Université de Bordeaux, F-33000 Bordeaux, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Genot
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada boris.hinz@utoronto.ca.
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism / Q000502:physiology; D040542:Mechanotransduction, Cellular; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D016023:Integrins; D053773:Transforming Growth Factor beta1