Study of mouse models to study regression of liver fibrosis

Liver fibrosis is a progressive and potentially reversible condition resulting from chronic liver damage that can be caused by a variety of factors, including metabolic steatotic liver disease (MASLD), alcohol abuse, and viral hepatitis. MASLD affects a large proportion of the world’s population and can progress to metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis if left untreated. Given the prevalence of MASLD and related conditions, studying fibrosis and its regression has become crucial for the development of therapeutic interventions. This review provides a detailed examination of experimental mouse models used to study regression of liver fibrosis both in vivo and ex vivo, highlighting their relevance, advantages and limitations.

Liver fibrosis and fibrogenesis

Fibrogenesis is a wound healing response to long-term liver injury, characterized by extracellular matrix (ECM) deposition by activated hepatic stellate cells (HSCs) and myofibroblasts. Various irritants, including lipid overload and exposure to toxins, can lead to fibrosis. The molecular processes underlying fibrosis are complex, but inflammation caused by reactive oxygen species plays a critical role. It is important to note that fibrosis is not a static process; under certain conditions it is reversible as inflammatory reactions subside and degradation of the ECM occurs. Understanding these dynamics is important for developing treatments that promote fibrosis regression.

Mouse models for studying liver fibrosis

Mouse models provide a valuable platform for studying liver fibrosis, especially in the context of human MASLD. The review classifies models based on the fibrosis induction method as diet-induced models (eg, high-fat diets), genetic models, hepatotoxin-induced models, and models using biliary atresia or parasitic infections. These models vary in their ability to recapitulate fibrosis and regression of the human liver, each with its own advantages and limitations.

For example, while wild-type C57BL/6 mice fed a high-fat diet (HFD) develop mild fibrosis, genetic modifications (eg, LDL receptor knockout mice) and improved diets can accelerate the progression of fibrosis. Meanwhile, hepatotoxin-induced models using substances such as carbon tetrachloride (CCl4) provide rapid induction of fibrosis but do not fully recapitulate the metabolic abnormalities observed in humans. Despite these problems, these models play an important role in studying the regression of fibrosis after removal of fibrosis-inducing stimuli.

Reversible liver fibrosis in mouse models

One of the most important areas of focus in the review is reversible fibrosis. Some mouse models demonstrate regression of fibrosis after removal of the pathogen or through therapeutic intervention. The review highlights various methods for inducing reversible fibrosis, including CCl4 withdrawal, dietary modification, and genetic reconstitution techniques. While some models demonstrate nearly complete regression, others demonstrate variable or incomplete resolution of fibrosis, often reflecting the clinical variability observed in human patients.

For example, in CCl4-induced models, fibrosis regression can be almost complete after four to eight weeks of CCl4 withdrawal, depending on the mouse strain used. In contrast, models involving diet-induced fibrosis often show partial regression, highlighting the difficulty of reversing liver damage caused by metabolic dysfunction.

Ex vivo and in vitro models

In addition to in vivo studies, ex vivo and in vitro approaches provide a controlled environment for studying fibrosis and its regression. Precision liver slices (PCLS) and liver organoids have been developed to study fibrosis at the cellular level, allowing researchers to test the effects of antifibrotic compounds. These models offer a bridge between in vivo studies and clinical applications, although they lack the complexity of whole organ interactions observed in living organisms.

Prospects

The future of liver fibrosis research lies in refining these models to more accurately simulate the progression and regression of human diseases. Technological advances such as non-invasive imaging and molecular markers will allow better real-time monitoring of fibrosis. In addition, the development of organoids and PCLS that more closely recapitulate human liver physiology may reduce the need for animal studies while providing valuable insight into the mechanisms of fibrosis.

Conclusions

Mouse models have made significant contributions to our understanding of liver fibrosis and the possibility of its regression. Although no model perfectly reproduces human disease, these experimental systems provide important insight into the cellular and molecular processes involved. Future research will continue to improve these models, leading to the development of more effective treatments for liver fibrosis and related conditions.