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.

Automated summary

Liver fibrosis is primarily caused by activated hepatic stellate cells (HSCs), and targeting these cells is crucial in preventing liver fibrosis. This study investigated the in vivo functions of thymosin beta 4 (T β 4) in liver fibrosis by generating T β 4 conditional knockout mice. The selective deletion of T β 4 in activated HSCs attenuated liver injury and fibrosis by repressing Hedgehog signaling. Re-expression of T β 4 reversed the effect of HSC-specific T β 4 deletion and led to liver fibrosis with Hedgehog activation. These findings suggest T β 4 as a potential therapeutic target for liver fibrosis.