Beyond ADME-Tox: Hepatocyte use for disease modeling

Human Hepatocytes in Disease Modeling

Use the table to determine what format of hepatocytes is best for your disease modeling efforts.

Hepatitis

Many varieties of the hepatitis virus cause inflammation of the liver, which can lead to severe illness or even death when left untreated. Millions of people are infected with hepatitis viruses worldwide and it remains a leading cause of hepatocellular carcinomas, especially in individuals born in the U.S.A. between 1945 and 1965. While cures have been developed for the deadliest variant, Hepatitis C (HCV), reinfection can occur because HCV is very prone to mutation. This tendency to mutate has also hindered the development of a HCV vaccine. While an effective vaccine is available for the more common Hepatitis B (HBV) virus, it still infects millions annually and causes illnesses ranging from flu-like symptoms to liver failure. HBV is a DNA virus that utilizes the nuclear machinery of the hepatocyte to replicate. Infection and subsequent replication can be modeled in primary human hepatocytes in culture, and has been used to develop large scale screening protocols for new drugs that attack the progression of the virions to the closed circular DNA, which eventually leads to inflammation and other symptoms. So far, HBV has eluded efforts to develop curative drugs. (4) For hepatitis studies in vitro, our hepatocytes prequalified to be plateable for 5 days in culture are ideal. These include the General Purpose (HUCPG), Induction Qualified (HUCPI), and Transporter Qualified (HUCPQ) cells.

Malaria

Nearly half of the world’s population lives in regions where inhabitants are at risk for malaria infection and more than 500,000 people worldwide die from the disease each year. Malaria is caused by a Plasmodium parasite, which has a life cycle that includes the human liver; specifically, the infection of hepatocytes. As shown in Figure 4, Plasmodium sporozoites undergo a major replication event in the hepatocyte before entering the next stage of the life cycle in the blood. Once the parasite is in the blood, the infected person begins to experience the symptoms associated with malaria; alternating chills and fever, fatigue, and others. The development of clinical interventions for the liver stage of the Plasmodium life cycle has become of interest, not only to prevent malaria symptoms, but also the spread of the parasite back to the mosquito, through the blood. For hepatitis studies in vitro, our hepatocytes prequalified to be plateable for 5 days in culture are ideal. These include the General Purpose (HUCPG), Induction Qualified (HUCPI), and Transporter Qualified (HUCPQ) cells.

The challenge of using hepatocytes for research on Plasmodium infection has been that the hepatocytes must survive for several weeks in culture. Recent work has shown that co-cultures of cryopreserved hepatocytes with liver Kupffer cells (i.e., the resident macrophage in the liver) (HLKC) can successfully mimic the liver stage of the Plasmodium life cycle. (11).

Non-alcoholic steatohepatitis (NASH) models

Non-alcoholic steatohepatitis (NASH) is a disease of the liver characterized by the infiltration of inflammatory cells, increased lipidosis in the hepatocytes, and early stages of collagen deposition leading to fibrosis. NASH is a progression of non-alcoholic fatty liver disease (NAFLD), which is associated with obesity and diabetes. The incidence of NAFLD is thought to be as high as 30% of the population and continues to rise with the co-incident rise in obesity.

The interest in developing cell-culture models for NASH is very high. Currently, a non-invasive diagnostic is not available for NASH and effective treatments are still in the early research and development stages. However, the onset of fibrosis, which is characterized by increased collagen deposition, is a hallmark pathological feature of NASH. Cell models that recapitulate the features of NASH contain both hepatocytes and stellate cells in co-culture or in 3D models. (12) For NASH studies in vitro, our hepatocytes prequalified to be plateable for 5 days in culture are ideal. These include the General Purpose (HUCPG), Induction Qualified (HUCPI), and Transporter Qualified (HUCPQ) cells. Researchers may also be interested in low-passage Stellate cells (HUCLS), Kupffer cells (HLKC), and liver endothelial cells (HLECP2) for building physiologically relevant 3D culture models to mimic the progression of NASH in vitro.