Targeted Deletion of Thymosin Beta 4 in Hepatic Stellate Cells Ameliorates Liver Fibrosis in a Transgenic Mouse Model

Liver fibrosis is the most common feature of liver disease, and activated hepatic stellate cells (HSCs) are the main contributors to liver fibrosis. Thus, finding key targets that modulate HSC activation is important to prevent liver fibrosis. Previously, we showed that thymosin beta 4 (T beta 4) influenced HSC activation by interacting with the Hedgehog pathway in vitro. Herein, we generated T beta 4 conditional knockout (T beta 4-flox) mice to investigate in vivo functions of T beta 4 in liver fibrosis. To selectively delete T beta 4 in activated HSCs, double-transgenic (DTG) mice were generated by mating T beta 4-flox mice with alpha-smooth muscle actin (alpha-Sma)-Cre-ERT2 mice, and these mice were administered carbon tetrachloride (CCl4) or underwent bile duct ligation to induce liver fibrosis. T beta 4 was selectively suppressed in the activated HSCs of DTG mouse liver, and this reduction attenuated liver injury, including fibrosis, in both fibrotic models by repressing Hedgehog (Hh) signaling. In addition, the re-expression of T beta 4 by an adeno-associated virus reversed the effect of HSC-specific T beta 4 deletion and led to liver fibrosis with Hh activation in CCl4-exposed mice treated with tamoxifen. In conclusion, our results demonstrate that T beta 4 is a crucial regulator of HSC activation, suggesting it as a novel therapeutic target for curing liver fibrosis.