Hepatic stellate cells play an vital function in regeneration and fibrosis after liver damage, however the goal genes that concurrently regulate each processes in hepatic stellate cells should not but clear. Credit score: Prof. Wang’s staff
A analysis staff has recognized the transcription issue Lhx2 (LIM homeobox protein 2) as a key regulator in hepatic stellate cells. Lhx2 was discovered to concurrently promote liver regeneration and inhibit liver fibrosis.
The research was led by the Guangzhou Institutes of Biomedicine and Well being of the Chinese language Academy of Sciences, in collaboration with the Japanese Hepatobiliary Surgical procedure Hospital of the Second Army Medical College, and was printed within the journal Hepatology.
The liver is the human physique’s most regenerative stable organ. Nevertheless, persistent liver damage can severely impair this regenerative capability, resulting in liver fibrosis. Hepatic stellate cells (HSCs), the liver’s major mesenchymal cells, play a essential function in each regeneration and fibrosis. Regardless of their significance, it stays unclear whether or not particular genes in HSCs can concurrently promote regeneration and inhibit fibrosis.
On this research, the researchers in contrast liver pathological phenotypes and hepatic stellate cell (HSC) expression profiles throughout the restore part following acute and persistent liver damage. They found that HSCs are essential regulators of liver regeneration and fibrosis.
Utilizing differential transcription issue screening and public single-cell transcriptomic information, they recognized the transcription issue Lhx2 in HSCs as a dual-function regulator of liver regeneration and fibrosis. Additional evaluation with RNA-seq and CUT&Tag revealed that Lhx2 upregulates regenerative components whereas suppressing genes linked to HSC activation.
To validate Lhx2’s operate on the animal stage, the staff developed mouse fashions of acute and persistent liver damage utilizing CCl4. By injecting modified si-RNAs, they demonstrated that Lhx2 knockdown impaired hepatocyte proliferation and liver operate restoration after acute damage.
Moreover, utilizing Lrat-cre (HSC-specific cre) mice and AAV8-DIO-mLhx2 virus, they overexpressed Lhx2 particularly in HSCs, confirming that Lhx2 promotes liver regeneration and restore after acute damage whereas inhibiting fibrosis in persistent damage.
On the molecular stage, Lhx2 was discovered to advertise hepatocyte proliferation by upregulating HGF expression in HSCs. It additionally inhibited HSC activation and fibrosis by upregulating SMAD6, which blocks the TGF-β signaling pathway.
This research systematically demonstrated the essential function of HSCs in liver regeneration and fibrosis on the molecular, mobile, and animal ranges. It additionally elucidated the molecular mechanisms by which Lhx2 regulates these processes, providing new insights for the remedy of liver ailments.
Extra info:
Jiawang Tao et al, Lhx2 particularly expressed in HSCs promotes liver regeneration and inhibits liver fibrosis, Hepatology (2024). DOI: 10.1097/HEP.0000000000001201
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Researchers establish Lhx2 as key gene in hepatic stellate cells regulating liver regeneration and fibrosis (2025, February 18)
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