title: Artificial extracellular matrix composed of collagen I and highly sulfated hyaluronan interferes with TGFβ(1) signaling and prevents TGFβ(1)-induced myofibroblast differentiation.
abstract: Sulfated glycosaminoglycans are promising components for functional biomaterials since sulfate groups modulate the binding of growth factors and thereby influence wound healing. Here, we have investigated the influence of an artificial extracellular matrix (aECM) consisting of collagen I (coll) and hyaluronan (HA) or highly sulfated HA (hsHA) on dermal fibroblasts (dFb) with respect to their differentiation into myofibroblasts (MFb). Fibroblasts were cultured on aECM in the presence of aECM-adsorbed or soluble transforming growth factor β1 (TGFβ1). The synthesis of α-smooth muscle actin (αSMA), collagen and the ED-A splice variant of fibronectin (ED-A FN) were analyzed at the mRNA and protein levels. Furthermore, we investigated the bioactivity and signal transduction of TGFβ1 in the presence of aECM and finally made interaction studies of soluble HA or hsHA with TGFβ1. Artificial ECM composed of coll and hsHA prevents TGFβ1-stimulated αSMA, collagen and ED-A FN expression. Our data suggest an impaired TGFβ1 bioactivity and downstream signaling in the presence of aECM containing hsHA, shown by massively reduced Smad2/3 translocation to the nucleus. These data are explained by in silico docking experiments demonstrating the occupation of the TGFβ-receptor I binding site by hsHA. Possibly, HA sulfation has a strong impact on TGFβ1-driven differentiation of dFb and thus could be used to modulate the properties of biomaterials.
authors.affiliation: Department of Dermatology, Venereology and Allergology, Leipzig University, 04103 Leipzig, Germany. anja.vandersmissen@medizin.uni-leipzig.de
authors.forename: Anja
authors.initials: A
authors.lastname: van der Smissen
authors.forename: Sergey
authors.initials: S
authors.lastname: Samsonov
authors.forename: Vera
authors.initials: V
authors.lastname: Hintze
authors.forename: Dieter
authors.initials: D
authors.lastname: Scharnweber
authors.forename: Stephanie
authors.initials: S
authors.lastname: Moeller
authors.forename: Matthias
authors.initials: M
authors.lastname: Schnabelrauch
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pisabarro
authors.forename: Ulf
authors.initials: U
authors.lastname: Anderegg
mesh_terms: D040761:Biomimetic Materials / Q000737:chemistry*; D002454:Cell Differentiation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000737:chemistry*; D005109:Extracellular Matrix / Q000737:chemistry*; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D008422:Materials Testing; D058628:Myofibroblasts / Q000166:cytology* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013431:Sulfates / Q000737:chemistry; D013499:Surface Properties; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D013431:Sulfates; D053773:Transforming Growth Factor beta1; D006820:Hyaluronic Acid