Modelling metabolic diseases and drug response using stem cells and organoids
Metabolic diseases, including obesity, diabetes mellitus and cardiovascular disease, are a major threat to healgth in the modern world, but efforts to understand the underlying mechanisms and develop rational treatments are limited by the lack of appropriate human model systems. Notably, advances in stem cell and organoid technology allow the generation of cellular models that replicate the histological, molecular and physiological properties of human organs.
There are three main types of adipocytes: lipid-filled white adipocytes, metabolically healthy inducible beige (or brite) adipocytes and thermogenic and mitochondrial-enriched brown adipocytes. obesityMost studies have focused on studying adipose tissue using rodent models, which have identified numerous potential therapeutic targets for treating obesity and metabolic disease. For example, the activity of human BAT is driven by the β2 adrenergic receptor, in contrast to the β3 adrenergic receptor in adipose tissue of mice. Thus, there is a great need to generate mature human adipocytes, or adipose organoid systems that model the complexity and crosstalk of different cell types within adipose tissue, to develop new therapeutic strategies for adipose-related metabolic diseases. Thus, obesity is highly related to non-alcoholic fatty liver disease (NAFLD), which can progress from steatosis to more advanced non-alcoholic steatohepatitis (NASH) that is characterized by progressive inflammation and fibrosis. NASH is a precursor of hepatocellular carcinoma as well as liver failure. However, there is currently no FDA-approved therapy for NASH. Numerous cellular models and animal models have been used to explore the underlying mechanisms of liver development and pathogenesis, but little progress has been made towards developing successful therapeutic strategies for liver diseases, especially NASH, due to the limitations of traditional cellular and animal model.
In the past decade, the modelling of human physiology and disease has benefited from the development of organoids.
Hu, W., Lazar, M.A. Modelling metabolic diseases and drug response using stem cells and organoids. Nat Rev Endocrinol (2022). https://doi.org/10.1038/s41574-022-00733-z
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