title: Heparin-binding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix.
abstract: By binding growth factors (GFs), the ECM tightly regulates their activity. We recently reported that the heparin-binding domain II of fibronectin acts as a promiscuous high-affinity GF-binding domain. Here we hypothesized that fibrin, the provisional ECM during tissue repair, also could be highly promiscuous in its GF-binding capacity. Using multiple affinity-based assays, we found that fibrin(ogen) and its heparin-binding domain bind several GFs from the PDGF/VEGF and FGF families and some GFs from the TGF-β and neurotrophin families. Overall, we identified 15 unique binding interactions. The GF binding ability of fibrinogen caused prolonged retention of many of the identified GFs within fibrin. Thus, based on the promiscuous and high-affinity interactions in fibrin, GF binding may be one of fibrin's main physiological functions, and these interactions may potentially play an important and ubiquitous role during tissue repair. To prove this role in a gain-of-function model, we incorporated the heparin-binding domain of fibrin into a synthetic fibrin-mimetic matrix. In vivo, the multifunctional synthetic matrix could fully mimic the effect of fibrin in a diabetic mouse model of impaired wound healing, demonstrating the benefits of generating a hybrid biomaterial consisting of a synthetic polymeric scaffold and recombinant bioactive ECM domains. The reproduction of GF-ECM interactions with a fibrin-mimetic matrix could be clinically useful, and has the significant benefit of a more straightforward regulatory path associated with chemical synthesis rather than human sourcing.
authors.affiliation: Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Mikaël M
authors.initials: MM
authors.lastname: Martino
authors.forename: Priscilla S
authors.initials: PS
authors.lastname: Briquez
authors.forename: Adrian
authors.initials: A
authors.lastname: Ranga
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Lutolf
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D005109:Extracellular Matrix; D005337:Fibrin / Q000737:chemistry / Q000494:pharmacology*; D005340:Fibrinogen / Q000737:chemistry / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011485:Protein Binding; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D005337:Fibrin; D005340:Fibrinogen