Researchers Develop Stem Cell-based in vitro Model of Nonalcoholic Fatty Liver Disease

Researchers Develop Stem Cell-based in vitro Model of Nonalcoholic Fatty Liver Disease

A team of researchers at the Institute for Stem Cell Research and Regenerative Medicine at University Hospital Duesseldorf has developed a stem cell-based cell culture for studying nonalcoholic fatty liver disease (NAFLD).

NAFLD is the term given to a range of conditions that cause a buildup of fat in the liver. Individuals with NAFLD have lipid droplets in the liver which decrease the ability of the liver to function. NAFLD is common in people in the Western world and affects around 30% of populations, most commonly people who are overweight or obese, although the exact cause of NAFLD is not well understood. There is no approved therapy for NAFLD, only medications that can help manage problems associated with the disease.

The research team, led by Dr. Nina Graffman, differentiated induced pluripotent stem cells (IPSCs) from healthy and NAFLD patients into hepatocyte-like cells (HLCs). Under stimulation using fatty acids to mimic a diet containing excess fat, lipid droplets were produced in the HLCs as occurs in the livers of NAFLD patients. The largest lipid droplets were observed in the healthy control donor group.

The research team demonstrated strong heterogeneity between cell lines regarding gene expression and lipid droplet morphology, which the researchers attribute to the many metabolic networks that are involved in NAFLD, although the researchers were able to identify patterns in gene expression that correlate with the severity of the disease.

The researchers attempted to reverse the steatosis in the HSCs using a synthetic analogue of Adiponectin. Adiponectin is a molecule synthesized by human fat cells that affects hepatocyte metabolism. The synthetic analogue – AdipoRon – developed by Prof. Constantin Czekelius and his team at the institute for Organic Chemistry and Macromolecular Chemistry at Heinrich-Heine-University Duesseldorf, had a general influence on metabolism, transport, immune system, cell stress and signalling, although there was variation in responses between cell lines.

“We could recapitulate important aspects of NAFLD with our stem cell-based cell culture model. We are going to use it for further studies, because established animal models cannot reproduce the complex human metabolic pathways involved in the development of the disease,” said Dr. Graffman.

Professor James Adjaye said, “Once again we have shown that although iPSC- derived hepatocyte-like cells are immature in nature, i.e., fetal, these cells still have immense usefulness in their application in drug discovery and for dissecting disease mechanisms such as NAFLD.”

You can read more about the study in the paper – A stem cell based in vitro model of NAFLD enables the analysis of patient specific individual metabolic adaptations in response to a high fat diet and AdipoRon interference – which was recently published in Biology Open. DOI: 10.1242/bio.054189