Non-alcoholic fatty liver disease (NAFLD) is the most chronic form of liver disease, which affects about quarter of the population in the US. Nearly half of the patients suffering from NAFLD can progress to non-alcoholic steatohepatitis (NASH), an inflammatory syndrome which disrupts the liver’s function. Some of the changes occurring in NAFLD includes lipid deposition, fibrosis, collagen deposition and adjacent deleterious processes. NASH and other inflammatory liver diseases have been a bigger problem, and continue to grow in prevalence, with very fewer promising treatments available. NASH is defined as liver manifestation of the metabolic disorder problems. The symptoms are silent, and it often remains undiagnosed until the late stage of the disease. Thus, it is important to design various drug discovery assays to treat this problem.

The first approach for precision-cut liver slices used for the assessment of drug effect ex vivo is to get healthy, human donor liver tissue and to induce a disease state ex vivo by chemical/biochemical stimulation. Then, the liver is treated with compounds to evaluate potential amelioration of the disease. Another approach is to use diseased donor livers, and then treat the precision cut liver slices to evaluate compounds and their therapeutic effects. Lastly, a mouse induced with CCL-4 can form liver fibrosis, and that liver can be used to evaluate the therapeutic effects of different compounds.

For precision cut liver slices, once the liver is obtained slices are made using a compresstome and then incubated in 24 well plates with transwell inserts. The slices are treated with various compounds, after which various endpoints are measured to gauge the effectiveness of the compound.

NASH-NAFLD

Imaging endpoints for Visikol’s 3D Human NASH/Liver Fibrosis Model, showing DAPI (blue), pan-collagen (green) and α-smooth muscle actin (red). Spheroids containing human hepatocytes and non-parenchymal cells are treated with TGFβ1 to induce fibrosis. An ALK5 inhibitor serves as a negative control, co-treatment with the ALK5 inhibitor and TGFβ1 shows a similar level of collagen deposition as the vehicle control.

More about PCLS

  1. Healthy human liver tissue/Diseased human liver tissue

The healthy human liver tissue can be treated with TGf-β to induce fibrosis, and diseased liver tissue can be obtained from donors. Diseased liver has the advantage of being the most physiologically relevant model of liver disease, and different therapeutic compounds are tested with this liver model using precision liver cut slices. However, it takes time to receive the donor liver with all the fulfilled criteria.

  1. Mouse model of CCL-4 induced liver fibrosis

The most used model for liver fibrosis chemically induced in mice is to induce carbon tetrachloride (CCL4). This induction causes hepatocyte damage, necrosis, inflammation, and fibrosis after 4 weeks and can lead to cirrhosis after 8 weeks. This model mimics human fibrosis, and it can used for drug screening compounds to treat fibrosis.

Research is still ongoing for biomarker identification, and identifying the compounds to reduce biomarkers as there are no approved treatments available for NASH.  The team of scientists at Visikol have a wide range of expertise in different fields such as pharmacology and drug discovery to identify therapeutic compounds and perform various assays.

Visikol is one of the leaders in in vitro assays and an expert in 3D cell culture modeling and its quantitative evaluation of tissue imaging services is valuable. Visikol’s uniquely designed assays with advanced cell culturing techniques and high content imaging helps to enable quantitative evaluation of promising compounds in vitro. Contact us to get started today.

2022-06-29T07:36:47-05:00

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