Animal and Organoid Models of Liver Fibrosis

Abstract

Liver fibrosis refers to the process underlying the development of chronic liver diseases, wherein liver cells are repeatedly destroyed and regenerated, which leads to an excessive deposition and abnormal distribution of the extracellular matrix such as collagen, glycoprotein and proteoglycan in the liver. Liver fibrosis thus constitutes the pathological repair response of the liver to chronic injury. Hepatic fibrosis is a key step in the progression of chronic liver disease to cirrhosis and an important factor affecting the prognosis of chronic liver disease. Further development of liver fibrosis may lead to structural disorders of the liver, nodular regeneration of hepatocytes and the formation of cirrhosis. Hepatic fibrosis is histologically reversible if treated aggressively during this period, but when fibrosis progresses to the stage of cirrhosis, reversal is very difficult, resulting in a poor prognosis. There are many causes of liver fibrosis, including liver injury caused by drugs, viral hepatitis, alcoholic liver, fatty liver and autoimmune disease. The mechanism underlying hepatic fibrosis differs among etiologies. The establishment of an appropriate animal model of liver fibrosis is not only an important basis for the in-depth study of the pathogenesis of liver fibrosis but also an important means for clinical experts to select drugs for the prevention and treatment of liver fibrosis. The present study focused on the modeling methods and fibrosis characteristics of different animal models of liver fibrosis, such as a chemical-induced liver fibrosis model, autoimmune liver fibrosis model, cholestatic liver fibrosis model, alcoholic liver fibrosis model and non-alcoholic liver fibrosis model. In addition, we also summarize the research and application prospects concerning new organoids in liver fibrosis models proposed in recent years. A suitable animal model of liver fibrosis and organoid fibrosis model that closely resemble the physiological state of the human body will provide bases for the in-depth study of the pathogenesis of liver fibrosis and the development of therapeutic drugs.

IL-17A in Human Liver: Significant Source of Inflammation and Trigger of Liver Fibrosis Initiation

“…Most studies on IL-17A and liver fibrosis have been conducted on a mouse model [ 30 , 31 ]. The human case is much more complex due to intra- and inter-individual variability and the frequent presence of underlying disease.…”

Preclinical Long-term Magnetic Resonance Imaging Study of Silymarin Liver-protective Effects

“…We observed meaningful correlations between MRI-based values and the levels of several biomarkers. Carbon tetrachloride (CCl 4 ) is frequently used to induce liver failure, [40][41][42] but liver function occasionally occurs when CCl 4 administration is stopped. 42 Conversely, TAA damage persists for more than 2 months after withdrawal, and induces pathological characteristics similar to human chronic liver dysfunction.…”

Liver organoids: From fabrication to application in liver diseases

“…To demonstrate the difference between the TGFβ1-induced artificial liver fibrosis model and the liver fibrosis caused by the natural development of NAFLD, Ali et al established HepaRG-based bioengineered multicellular liver microtissues (BE-MLMs). HepaRG (cell line), HUVECs (human primary), KCs (human primary), and HSCs (human primary) were co-cultured in spheroid-laden hydrogels at different ratios while simulating liver tissue native configuration, such as nutrients/O 2 gradients and direct cell-cell contacts between different cell types inside spheroids ( Bao et al, 2021 ). Organoid of the HepaRG-based BE-MLMs is more complex and further describes the structural and metabolic environment of the liver.…”

“…Inflammation primarily activates hepatic stellate cells within the liver interstitium, which is the central event in liver fibrosis. Furthermore, hematopoietic stem cells are activated and differentiate into myofibroblasts, whose increase leads to the massive accumulation of ECM ( Bao et al, 2021 ). The chronic inflammatory process also produces several immune cells that are driven by inflammatory factors, which damages hepatocytes and causes them to lose their robust regenerative capacity, ultimately leading to the development of irreversible cirrhosis.…”