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Statistic Copolymers Working as Growth Factor-Binding Mimics of Fibronectin.

ABSTRACT: Growth factors (GFs) play important roles in biological system and are widely used in tissue regeneration. However, their application is greatly hindered by short in vivo lifetime of GFs. GFs are bound to fibronectin dynamically in the extracellular matrix, which inspired the authors to mimic the GF binding domain of fibronectin and design GF-binding amphiphilic copolymers bearing positive charges. The optimal amino acid polymer can bind to a variety of representative GFs, such as bone morphogenetic protein-2 (BMP-2) and TGF-β1 from the transforming growth factor-β superfamily, PDGF-AA and PDGF-BB from the platelet-derived growth factor family, FGF-10 and FGF-21 from the fibroblast growth factor family, epidermal growth factor from the EGF family and hepatocyte growth factor from the plasminogen-related growth factor family, with binding affinities up to the nanomolar level. 3D scaffolds immobilized with the optimal copolymer enable sustained release of loaded BMP-2 without burst release and significantly enhances the in vivo function of BMP-2 for bone formation. This strategy opens new avenues in designing GF-binding copolymers as synthetic mimics of fibronectin for diverse applications.

SUBMITTER: Zhang W

PROVIDER: S-EPMC9313494 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Statistic Copolymers Working as Growth Factor-Binding Mimics of Fibronectin.

Zhang Wenjing W Wu Yueming Y Chen Qi Q Zhang Haodong H Zhou Min M Chen Kang K Cao Chuntao C Guo Han H Xu Jianrong J Liu Honglai H Lin Haodong H Liu Changsheng C Liu Runhui R

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220515 21

Growth factors (GFs) play important roles in biological system and are widely used in tissue regeneration. However, their application is greatly hindered by short in vivo lifetime of GFs. GFs are bound to fibronectin dynamically in the extracellular matrix, which inspired the authors to mimic the GF binding domain of fibronectin and design GF-binding amphiphilic copolymers bearing positive charges. The optimal amino acid polymer can bind to a variety of representative GFs, such as bone morphogen ...[more]

PMID: 35570405

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Project description:Fibrosis is characterized by excessive production of disorganized collagen- and fibronectin-rich extracellular matrices (ECMs) and is driven by the persistence of myofibroblasts within tissues. A key protein contributing to myofibroblast differentiation is extra domain A fibronectin (EDA-FN). We sought to target and interfere with interactions between EDA-FN and its integrin receptors to effectively inhibit profibrotic activity and myofibroblast formation. Molecular docking was used to assist in the design of a blocking polypeptide (antifibrotic 38-amino-acid polypeptide, AF38Pep) for specific inhibition of EDA-FN associations with the fibroblast-expressed integrins α4β1 and α4β7. Blocking peptides were designed and evaluated in silico before synthesis, confirmation of binding specificity, and evaluation in vitro. We identified the high-affinity EDA-FN C-C' loop binding cleft within integrins α4β1 and α4β7. The polypeptide with the highest predicted binding affinity, AF38Pep, was synthesized and could achieve specific binding to myofibroblast fibronectin-rich ECM and EDA-FN C-C' loop peptides. AF38Pep demonstrated potent myofibroblast inhibitory activity at 10 µg/mL and was not cytotoxic. Treatment with AF38Pep prevented integrin α4β1-mediated focal adhesion kinase (FAK) activation and early signaling through extracellular-signal-regulated kinases 1 and 2 (ERK1/2), attenuated the expression of pro-matrix metalloproteinase 9 (MMP9) and pro-MMP2, and inhibited collagen synthesis and deposition. Immunocytochemistry staining revealed an inhibition of α-smooth muscle actin (α-SMA) incorporation into actin stress fibers and attenuated cell contraction. Increases in the expression of mRNA associated with fibrosis and downstream from integrin signaling were inhibited by treatment with AF38Pep. Our study suggested that AF38Pep could successfully interfere with EDA-FN C-C' loop-specific integrin interactions and could act as an effective inhibitor of fibroblast of myofibroblast differentiation.

Dataset Information

Statistic Copolymers Working as Growth Factor-Binding Mimics of Fibronectin.

Publications

Statistic Copolymers Working as Growth Factor-Binding Mimics of Fibronectin.

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