Table 2.
Mechanistic roles of key EMC components during liver fibrosis.
| ECM component | Receptors Mechanisms | Effects on cell function and fibrosis progression | Possible therapeutic target in liver fibrosis |
|---|---|---|---|
| Type I collagen | Integrin αv/β1/DDR1/DDR2 | αv signals activate latent TGFβ (235). β1 induces PAK/YAP signaling leading to HSC activation and liver fibrosis (73). DDR2 promotes HSC proliferation and invasion via MMP2 (71). |
Blocking αv attenuates liver fibrosis (69). PAK inhibition attenuates liver fibrosis (73). DDR2-deficient mice showed exacerbated hepatotoxin-induced liver fibrosis (70). |
| Arrestine, Tumstatin (fragments from Type IV collagen) | Integrin αv/β3 | suppresses endothelial cell proliferation, migration, angiogenesis (66, 67). | Tumstatin suppresses tumor growth (66). |
| Fibronectin | Integrin αvβ6 | Cholangiocytes proliferate, local TGFβ1 activation (236). | αvβ6 antagonist EMD527040 attenuates bile ductular proliferation and peribiliary collagen deposition (236). |
| Anastellin (fragments from fibronectin) | Binds to full-length fibronectin to form polymerized fibronectin multimers and inhibits cell migration (237). | Administration of polymeric fibronectin inhibits tumor growth, angiogenesis, and metastasis (238). | |
| Hyaluronic acid | CD44/TLR4/stab2 | Induces invasive phenotype of HSC via HA/CD44/Notch1 pathway. | Blocking HA production by 4-MU or HAS2 depletion prevents liver fibrosis (52). |
| laminin | Integrin | Supports proliferation and differentiation of hepatic progenitor cells in the fibrotic liver (38, 39). | Promotes progenitor cell differentiation of biliary phenotype (39). |
| elastin | Cross-linking of fibers. Elastin-derived peptide chemoattracts monocytes, fibroblasts, endothelial cells (45). | Relates to the irreversibility of liver fibrosis (44). | |
| Decorin | cMET (239) Binding to cytokines(240) |
Activates macrophages by interfering with TGFβ binding to macrophages (241). | Decorin acts as antifibrotic by binding TGF-β and controlling its bioactivity(242), and tumor repressor by binding PDGFRα (243). |
| Biglycan | TLR2/4 (244) Binding to cytokines(245) |
Proinflammatory activation of macrophages (244). |