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Organoids model human fatty liver disease

Scientists have developed a remarkable model of human fatty liver disease using human cells to generate spherical “organoids”—miniature livers in a dish with complex cellular and structural features. Fatty liver disease, or steatosis, can in some people progress to steatohepatitis, a form of fatty liver disease marked by inflammation and damage, as well as fat accumulation. One form of this disease—nonalcoholic steatohepatitis—is becoming increasingly common in both adults and children in the United States and other countries along with the rise in obesity. However, not all individuals with obesity develop the disease, and nonalcoholic steatohepatitis can sometimes occur in people who do not have obesity. Despite many animal model studies of the disease, no approved drugs have been developed to treat steatohepatitis, and treatment guidelines consist of advising individuals who have overweight or obesity to lose weight. In these experiments, scientists used several stem cell lines capable of forming multiple cell types from healthy men and women and from women and girls with liver disease, to create human liver organoids with multiple liver cell types, similar to the natural organ. With all these cell types, the organoids were functionally similar to human liver tissue in terms of their activation of genes, including those involved in fat metabolism. When treated with fatty acids to replicate high circulating levels of fats in the body due to excess fat tissue and/or a high-fat diet, the organoids showed many of the sequential features of human fatty liver disease. These features included fat accumulation, inflammation, and scar tissue formation, the last of which could be detected by measuring the stiffness of the organoids, simulating stiffness measurements of liver scarring in humans. Finally, organoids created from the cells of children with a genetic form of severe steatohepatitis, called Wolman disease, showed many features of the disease found in humans, and responded favorably to a protein called fibroblast growth factor 19, which is known to be produced by intestinal cells in response to a drug being tested as a fatty liver disease treatment. This research provides a new path forward to study human fatty liver disease in a more personalized way, using cells from individuals to create organoids, and may enable future discovery of effective treatments for this disease.

Ouchi R, Togo S, Kimura M,…Takebe T. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metab 30: 374-384.e6, 2019.

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