Journal
JOURNAL OF CELL SCIENCE
Volume 131, Issue 5, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.201293
Keywords
Myofibroblast; Fibrosis; Wound healing; Transforming growth factor beta 1; TGF-beta 1; Growth factor activation
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [375597, 210820, 286920, 286720]
- CIHR [413783]
- Natural Sciences and Engineering Research Council of Canada [413783]
- Canada Foundation for Innovation [26653, 36050]
- Ontario Research Fund (CFI/ORF) [26653, 36050]
- E-Rare Joint Transnational Program 'Development of Innovative Therapeutic Approaches for Rare Diseases' [ERL-138395]
- US National Institutes of Health [DK-058123, HL085083]
- European Union [237946]
- CIHR Cell Signals Training program
- NIH [F30-DK081265-01]
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organization for Scientific Research)
- CIHR
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Dysregulated secretion and extracellular activation of TGF-beta 1 stimulates myofibroblasts to accumulate disordered and stiff extracellular matrix (ECM) leading to fibrosis. Fibronectin immobilizes latent TGF-beta-binding protein-1 (LTBP-1) and thus stores TGF-beta 1 in the ECM. Because the ED-A fibronectin splice variant is prominently expressed during fibrosis and supports myofibroblast activation, we investigated whether ED-A promotes LTBP-1-fibronectin interactions. Using stiffness-tuneable substrates for human dermal fibroblast cultures, we showed that high ECM stiffness promotes expression and colocalization of LTBP-1 and ED-A-containing fibronectin. When rescuing fibronectin-depleted fibroblasts with specific fibronectin splice variants, LTBP-1 bound more efficiently to ED-A-containing fibronectin than to ED-B-containing fibronectin and fibronectin lacking splice domains. Function blocking of the ED-A domain using antibodies and competitive peptides resulted in reduced LTBP-1 binding to ED-A-containing fibronectin, reduced LTBP-1 incorporation into the fibroblast ECM and reduced TGF-beta 1 activation. Similar results were obtained by blocking the heparin-binding stretch FNIII 12-13-14 (HepII), adjacent to the ED-A domain in fibronectin. Collectively, our results suggest that the ED-A domain enhances association of the latent TGF-beta 1 by promoting weak direct binding to LTBP-1 and by enhancing heparin-mediated protein interactions through HepII in fibronectin.
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