title: Disentangling the multifactorial contributions of fibronectin, collagen and cyclic strain on MMP expression and extracellular matrix remodeling by fibroblasts.
abstract: Early wound healing is associated with fibroblasts assembling a provisional fibronectin-rich extracellular matrix (ECM), which is subsequently remodeled and interlaced by type I collagen. This exposes fibroblasts to time-variant sets of matrices during different stages of wound healing. Our goal was thus to gain insight into the ECM-driven functional regulation of human foreskin fibroblasts (HFFs) being either anchored to a fibronectin (Fn) or to a collagen-decorated matrix, in the absence or presence of cyclic mechanical strain. While the cells reoriented in response to the onset of uniaxial cyclic strain, cells assembled exogenously added Fn with a preferential Fn-fiber alignment along their new orientation. Exposure of HFFs to exogenous Fn resulted in an increase in matrix metalloproteinase (MMP) expression levels, i.e. MMP-15 (RT-qPCR), and MMP-9 activity (zymography), while subsequent exposure to collagen slightly reduced MMP-15 expression and MMP-9 activity compared to Fn-exposure alone. Cyclic strain upregulated Fn fibrillogenesis and actin stress fiber formation, but had comparatively little effect on MMP activity. We thus propose that the appearance of collagen might start to steer HFFs towards homeostasis, as it decreased both MMP secretion and the tension of Fn matrix fibrils as assessed by Fluorescence Resonance Energy Transfer. These results suggest that HFFs might have a high ECM remodeling or repair capacity in contact with Fn alone (early event), which is reduced in the presence of Col1 (later event), thereby down-tuning HFF activity, a processes which would be required in a tissue repair process to finally reach tissue homeostasis.
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Foolen
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Schoen
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Alberto
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Cartilage Engineering+Regeneration, Department of Health Sciences and Technology, ETH Zurich, Otto-Stern-Weg 7, CH-8093 Zurich, Switzerland.
authors.forename: Marcy
authors.initials: M
authors.lastname: Zenobi-Wong
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland. Electronic address: viola.vogel@hest.ethz.ch.
authors.forename: Viola
authors.initials: V
authors.lastname: Vogel
mesh_terms: D001696:Biomechanical Phenomena; D003094:Collagen / Q000097:blood / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005109:Extracellular Matrix / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000097:blood / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007091:Image Processing, Computer-Assisted; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014945:Wound Healing / Q000502:physiology*
chemical_list: D017931:DNA Primers; D005353:Fibronectins; D003094:Collagen; D020782:Matrix Metalloproteinases
keywords: Cyclic stretching; FRET-based molecular tension sensors; Human foreskin fibroblasts; Matrix metalloproteinases; Mechanobiology