Recombinant Fibronectin Matrix Mimetics Specify Integrin Adhesion and Extracellular Matrix Assembly

Abstract

Tissue engineering seeks to create functional tissues and organs by integrating natural or synthetic scaffolds with bioactive factors and cells. Creating biologically active scaffolds that support key aspects of tissue regeneration, including the re-establishment of a functional extracellular matrix (ECM), is a challenge currently facing this field. During tissue repair, fibronectin is converted from an inactive soluble form into biologically active ECM fibrils through a cell-dependent process. ECM fibronectin promotes cell processes critical to tissue regeneration and regulates the deposition and organization of other ECM proteins. We previously developed biomimetics of ECM fibronectin by directly coupling the heparin-binding fragment of the first type III repeat of fibronectin (FNIII1H) to the integrin-binding repeats (FNIII8-10). As adhesive substrates, fibronectin matrix mimetics promote cell growth, migration, and contractility through a FNIII1H-dependent mechanism. Here, we analyzed fibronectin matrix mimetic variants designed to include all or part of the integrin-binding domain for their ability to support new ECM assembly. We found that specific modifications of the integrin-binding domain produced adhesive substrates that selectively engage different integrin receptors to, in turn, regulate the amount of fibronectin and collagen deposited into the ECM. The ability of fibronectin matrix mimetics to direct cellsubstrate interactions and regulate ECM assembly makes them promising candidates for use as bioactive surfaces, where precise control over integrin-binding specificity and ECM deposition are required.

The miR-181d-regulated metalloproteinase Adamts1 enzymatically impairs adipogenesis via ECM remodeling

“…4,10,38 The function of adipose tissue is regulated by physiological interactions between cells and ECM miR-181d-regulated Adamts1 impairs adipogenesis S-Z Chen et al proteins. 4,39,40 Adipocyte differentiation requires space expansion, which stems from ECM remodeling. 4,38 ECM remodeling is regulated by a variety of modifiers, together with their respective enhancers and inhibitors.…”

Fibronectin Matrix Mimetics Promote Full-Thickness Wound Repair in Diabetic Mice

“…24 Fibronectin matrix mimetics stimulate these cell functions through an FNIII1H-dependent mechanism, while specific modifications to the integrinbinding domain enable selective engagement of different integrin receptors. 25 Cell adhesion to GST/III1H,8-10, which contains the complete cell-binding domain, 26 is mediated by a5b1 integrins. 25 Removing FNIII9 (GST/III1H,8,10) results in cell adhesion via both a5b1 and avb3 integrins.…”

“…25 Cell adhesion to GST/III1H,8-10, which contains the complete cell-binding domain, 26 is mediated by a5b1 integrins. 25 Removing FNIII9 (GST/III1H,8,10) results in cell adhesion via both a5b1 and avb3 integrins. 25 Deleting FNIII10 and inserting the GRGDSP loop into FNIII8 (GST/ III1H,8 RGD ) results in cell adhesion that is mediated exclusively by avb3 integrins.…”

“…25 Removing FNIII9 (GST/III1H,8,10) results in cell adhesion via both a5b1 and avb3 integrins. 25 Deleting FNIII10 and inserting the GRGDSP loop into FNIII8 (GST/ III1H,8 RGD ) results in cell adhesion that is mediated exclusively by avb3 integrins. 25 ECM fibronectin, as well as a5b1 and avb3 integrins have been implicated as key mediators of cutaneous wound healing.…”

Development of an Effective Cell Seeding Technique: Simulation, Implementation, and Analysis of Contributing Factors

“…Interestingly, previous studies also demonstrated that fibronectin-coated scaffolds facilitate cell proliferation as well as neotissue formation, supporting use of bioactive scaffolds for TE application. 35,38 Increasing scaffold thickness reduced the CSE response, whereas it had negligible effect on the DM. The scaffold thickness range (1.7 and 3.1 mm) used in this study reflected the anticipated application, which is for human knee cartilage where the thickness is roughly between 2 and 3 mm.…”