Scientists Identify Key Genes in Hepatic Stellate Cells That Regulate Liver Regeneration And Fibrosis

Promoting liver regeneration and inhibiting fibrosis is an attractive strategy for treating human liver diseases, and hepatic stellate cells (HSCs) are very important for both processes. Recently, in a research report entitled "Lhx2 specifically expressed in HSCs promotes liver regeneration and inhibits liver fibrosis" published in the international journal Hepatology, scientists from the Chinese Academy of Sciences identified the transcription factor Lhx2 (LIM homeobox protein 2) as a key regulator of hepatic stellate cells (HSCs). Lhx2 can simultaneously promote liver regeneration and inhibit liver fibrosis.

The liver is the most regenerative solid organ in the human body. However, chronic liver damage can severely impair this regenerative ability, leading to liver fibrosis. As the primary mesenchymal cells of the liver, hepatic stellate cells (HSCs) play a key role in liver regeneration and fibrosis. Despite their importance, researchers do not know whether specific genes in hepatic stellate cells promote liver regeneration and inhibit fibrosis at the same time.

In this study, researchers compared the pathological phenotype of livers in the repair phase after acute and chronic liver injury and the expression profile characteristics of hepatic stellate cells. The results showed that hepatic stellate cells are key regulators of liver regeneration and fibrosis in the body. By performing different transcription factor screening and publicly available single-cell transcriptomics data analysis, researchers identified a transcription factor called Lhx2 in hepatic stellate cells that may serve as a dual-function regulator of liver regeneration and fibrosis. Moreover, after further analysis using RNA sequencing and CUT&Tag (Cleavage Under Targets and Tagmentation), the researchers found that Lhx2 can upregulate the expression of regeneration factors while also inhibiting genes associated with hepatic stellate cell activation.

Figure 1. Lhx2 specifically expressed in HSCs promotes liver regeneration and inhibits liver fibrosis. (Tao J, et al. Hepatology)

To verify the function of Lhx2 at the animal level, the researchers used CCl4 to develop a mouse model of acute and chronic liver injury. By injecting modified siRNAs, they found that knockdown of Lhx2 impaired the proliferation of hepatocytes and the recovery of liver function after acute injury. In addition, using Lrat-cre (hepatic stellate cell-specific cre) mice and AAV8-DIO-mLhx2 virus, the researchers specifically overexpressed Lhx2 in hepatic stellate cells, confirming that Lhx2 can promote liver regeneration and repair after acute injury, while inhibiting liver fibrosis after chronic injury.

At the molecular level, the researchers found that Lhx2 can promote the proliferation of hepatocytes by upregulating the expression of HGF in hepatic stellate cells. It can also inhibit the activation of hepatic stellate cells and the occurrence of fibrosis by upregulating the SMAD6 molecule that blocks the TGF-β signaling pathway. This study systematically elucidates the key role of hepatic stellate cells in liver regeneration and fibrosis at the molecular, cellular and animal levels. At the same time, the molecular mechanisms behind Lhx2 regulating these processes were also clarified, which is expected to provide new insights for the development of new therapies for human liver diseases.

In summary, these research results show that Lhx2 has the functions of promoting liver regeneration and anti-fibrosis. At the same time, the researchers clarified the regulatory mechanism behind it, and also provided a potential promising therapeutic target with dual effects for the treatment of liver diseases.