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

Blood Advances
Shahrouz GhafooryJasimuddin Ahamed

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 (PF4CreTgfb1 f/f ) with carbon tetrachloride (CCl4), an inducer of acute hepatic injury and chronic fibrosis. CCl4 elicited equivalent hepatic injury in WT and PF4CreTgfb1 f/f mice based on loss of cytochrome P450 (Cyp2e1) expression, observed at 6 hours and peaking at 3 days after CCl4 challenge; PF4CreTgfb1 f/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 PF4CreTgfb1 f/f , mice, suggesting that increased TGF-β1 levels originated from platelet-released ...Continue Reading

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