Platelet TGF-β1 deficiency decreases liver fibrosis in a mouse model of liver injury

Abstract

Abstract: Transforming growth factor-β1 (TGF-β1) signaling in hepatic stellate cells (HSCs) plays a primary role in liver fibrosis, but the source of TGF-β1 is unclear. Because platelets are rich in TGF-β1, we examined the role of platelet TGF-β1 in liver fibrosis by challenging wild-type (WT) mice and mice deficient in platelet TGF-β1 (PF4CreTgfb1f/f) with carbon tetrachloride (CCl4), an inducer of acute hepatic injury and chronic fibrosis. CCl4 elicited equivalent hepatic injury in WT and PF4CreTgfb1f/f mice based on loss of cytochrome P450 (Cyp2e1) expression, observed at 6 hours and peaking at 3 days after CCl4 challenge; PF4CreTgfb1f/f mice exhibited less liver fibrosis than control mice. Activated platelets were observed during acute liver injury (6 hours), and WT mice with transient platelet depletion (thrombocytopenia) were partially protected from developing fibrosis compared with control mice (P = .01), suggesting an association between platelet activation and fibrosis. Transient increases in TGF-β1 levels and Smad2 phosphorylation signaling were observed 6 hours and 3 days, respectively, after CCl4 challenge in WT, but not PF4CreTgfb1f/f, mice, suggesting that increased TGF-β1 levels originated from platelet-released TGF-β1 during the initial injury. Numbers of collagen-producing HSCs and myofibroblasts were higher at 3 days and 36 days, respectively, in WT vs PF4CreTgfb1f/f mice, suggesting that platelet TGF-β1 may have stimulated HSC transdifferentiation into myofibroblasts. Thus, platelet TGF-β1 partially contributes to liver fibrosis, most likely by initiating profibrotic signaling in HSCs and collagen synthesis. Further studies are required to evaluate whether blocking platelet and TGF-β1 activation during acute liver injury prevents liver fibrosis.