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.

Keywords: animal; fibrosis; liver; model; organoid.

FIGURE 1

The mechanism of liver fibrosis. Liver damage can be caused by a variety of factors (e.g., chemical poisons, viruses, alcohol, nutrition, genetics, parasites, etc.). Injuries of liver cells release a variety of cytokines, among which damage-associated molecular patterns(DAMPs) (such as S100 family, high mobility group protein, etc.) can activate Kuffers (KCs) cells to produce inflammatory cytokines. Inflammatory cytokines can play a role through autocrine and paracrine. At this point, vascular permeability at the injured site increases, vascular endothelium simultaneously expresses high adhesion molecules, and inflammatory cells in the blood chemotaxis to the injured site under the action of chemokines, leading to the occurrence of inflammation. Multiple cytokines produced at the site of liver injury activate resting HSCs, causing HSCs to differentiate into myofibroblasts and produce ECM deposition. If the injury and inflammation are persistent or recurring, the deposition of ECM cannot be reversed, leading to liver fibrosis.

FIGURE 2

Organoid models of liver fibrosis. The generation of liver organoids and liver fibrosis models. liver organoid can be constructed by 3D co-culture of embryonic stem cells (ESC) and somatic hepatocytes, 3D coculture of induced pluripotent stem cells, and then through induction and differentiation of different developmental stages, and finally can be developed into liver organoids in the reactor. The establishment of liver fibrosis model using liver organoids can be used to study the mechanism of liver fibrosis and drug development and screening.

FIGURE 3

Timeline of animal and organoid liver fibrosis mode.