A research team carried out an animal study aimed at better understanding the scarring process (fibrosis) in diseased or injured livers. They examined gene activity in two different mouse models exhibiting varying degrees of liver disease severity, also capturing certain phases of spontaneous regression of the disease. At the same time, important indicators of disease severity, such as portal venous pressure, blood markers of liver injury, or the extent of liver fibrosis based on liver tissue samples, were recorded.
The scientists, led by Thomas Reiberger, MD, professor of gastroenterology and hepatology at MedUni Vienna and adjunct principal investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, published their results “Transcriptomic signatures of progressive and regressive liver fibrosis and portal hypertension” in iScience.
“Persistent liver injury triggers a fibrogenic program that causes pathologic remodeling of the hepatic microenvironment (i.e., liver fibrosis) and portal hypertension. The dynamics of gene regulation during liver disease progression and early regression remain understudied,” write the investigators.
“Here, we generated hepatic transcriptome profiles in two well-established liver disease models at peak fibrosis and during spontaneous regression after the removal of the inducing agents. We linked the dynamics of key disease readouts, such as portal pressure, collagen area, and transaminase levels, to differentially expressed genes, enabling the identification of transcriptomic signatures of progressive vs. regressive liver fibrosis and portal hypertension. Candidate biomarkers—Tcf4, Mmp7, Trem2, Spp1, Scube1, Islr—were validated in RNA sequencing datasets of patients with cirrhosis and portal hypertension, and those cured from hepatitis C infection.
“Finally, deconvolution identified major cell types and suggested an association of macrophage and portal hepatocyte signatures with portal hypertension and fibrosis area.”
Dynamic molecular processes can reverse liver fibrosis
A highly dynamic pattern of gene expression was observed, both during the development of fibrosis and, interestingly, also during the regression of liver fibrosis. Some genes were upregulated during the progression of the disease and downregulated during regression, while for others, it was the opposite. However, a number of genes showed persistent expression changes even during the regression phase, indicating long-lasting effects of liver damage.
Using bioinformatics methods, these genetic patterns were linked to the disease indicators described above. In doing so, the researchers identified genetic drivers of the disease that have potential as targets for the development of future therapies.
Through specially developed network algorithms, four important groups of genes were identified, which could be linked to the dynamics of fibrosis, portal venous pressure, histological data, and blood markers. These so-called “hub” genes could all be further developed into clinically relevant biomarkers. This was also tested and confirmed in the study with datasets from patients with liver diseases.
In collaboration with researchers from the University of Strasbourg and the Institut Universitaire de France, some of the hub genes were also confirmed in patients who were cured of hepatitis C, and thus had a regressed liver disease.
The study reveals genetic mechanisms in the development of liver fibrosis and offers new therapeutic possibilities to intervene in these mechanisms, according to the researchers. Further studies are needed to fully understand the potential of the hub genes and to use them for therapeutic strategies focusing on the regression of liver fibrosis, especially in patients with liver cirrhosis who adhere to alcohol abstinence or have been cured of viral hepatitis, they added.
