25 The multi-faceted extracellular matrix: unlocking its secrets for understanding the perpetuation of lung fibrosis Storage of growth factors in the ECM As the non-cellular part of the tissue microenvironment, the ECM serves as a storage depot for many different growth factors and other soluble proteins, many of which are important for regulating the fibrotic response. Within the ECM, it is predominantly the glycosaminoglycans (GAGs) that serve as a reservoir for growth factors in the extracellular space. The negatively charged residues within the GAGs provide multiple binding sites for the positively charged amino acids within many growth factors. Through these binding interactions the growth factors are bound to the ECM, protecting them from degradation and conserving them until they are required for local signaling [42, 43]. The changing protein content and organization in fibrotic lung diseases is likely to alter the presence, amount, and the availability of the factors stored within ECM. Among these ECM proteins, fibronectin can bind many growth factors and soluble proteins, including latent TGF-β-binding protein-1 (LTBP1) [44]. Increased amounts of fibronectin and LTBP-1 in fibrosis could lead to a greater storage capacity of ECM for TGF-β. Activation of the stored TGF-β can be directed via mechanical stimuli due to prestress on the ECM, applied by cells or decreased viscoelastic relaxation of the ECM itself [45]. TGF-β activation is also regulated by mechanisms driven by other proteins including fibulin-1, an ECM glycoprotein, which is also found in greater amounts in the lung tissues of IPF patients [46, 47]. The binding of growth factors important for lung development and repair, including TGF-β, fibroblast growth factor (FGF) 1 and FGF2 and hepatocyte growth factor (HGF), and their interaction with their relevant receptors are dependent on the sulfation state of GAGs such as heparan sulfate, dermatan sulfate and chondroitin sulfate [42, 48]. Using hydrogels established using decellularized lung ECM (which is devoid of most GAGs) combined with heparan sulfate, dermatan sulfate or chondroitin sulfate with either TGF-β, FGF2 or HGF, Uhl and colleagues recently illustrated that matrix associated growth factor-dependent and -independent GAG effects in parallel with GAG-dependent and -independent matrix-associated growth factor effects are important for regulating cellular responses in lung in vitro models [48]. There is an increase in heparan sulfate, chondroitin sulfate, dermatan sulfate and hyaluronan in IPF lungs compared to controls [49], suggesting a greater capacity for anchoring important growth factors for regulating reparative or fibrotic processes in these tissues. Analyses of the sulfation state of the GAGs in the IPF tissues found that the highly sulfated GAGs were located predominantly in the regions of interaction between the fibrotic and less fibrotic tissues, potentially indicating a central role for the GAGs in providing growth factors for promoting the high fibrotic activity within these regions. 2
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