Abstract

Functional Coupling of Human Pancreatic Islet Microtissues and Liver Spheroids in a Novel Micro-Physiological Multi-Organ System for Studies of Human Metabolic Diseases in Drug Discovery

Carina Ämmälä, Team leader, Cardiovascular, Renal and Metabolism, AstraZeneca

Multi organ-on-a-chip technologies, emulating human physiology and mimicking human disease states, could aid preclinical efforts by providing relevant translational models to validate targets and test tool compounds early in drug discovery. Such models have the potential to improve translation to patients, decrease time spent in early clinical programs and reduce the need for animal models.

Rodent studies have shown that insulin resistance causes hepatocytes to produce secreted factors that influence the islets. Whether similar cross talk exist in man remains to be determined. We therefore decided to develop a human liver - pancreatic islets chip model. Pancreatic islets and liver spheroids were applied in a two-organ microfluidic chip supplied by TissUse™ that allows cross talk between both organs. We have demonstrated that the model responds in a physiological way to a glucose load by increasing insulin secretion, which stimulates glucose consumption by the liver spheroids.  Both islet and liver spheroids show stable functionality as indicated by insulin secretion, albumin production and glucose consumption over the experimental period of two weeks. Initial results indicate that the liver spheroids can be made insulin resistant, altering hepatocyte transcriptome and secreted proteome, and thus represent a relevant metabolic disease model.