Modeling of obesity-induced metabolic changes by studying the crosstalk between human stem cell-derived pancreatic islets and liver organoids using a pump-less recirculating OoC (rOoC) platform
Shadab Abadpour1,2, Aleksandra AA Aizenshtadt2, Mathias MB Busek2,3, Chencheng CW Wang1,3, Stefan SG Gruenzner4, Alexey AG Golovin3, Justyna JS Stokowiec3, Hanne HS Scholz1,2, Stefan SK Karuss2,3.
1Department of Transplant Medicine and Institute for Surgical Research,, Oslo University Hospital, Oslo, Norway; 2Hybrid Technology Hub, , Institute of Basic Medical Science, University of Oslo, Oslo, Norway; 3Department of Immunology and Transfusion Medicine,, Oslo University Hospital, Oslo, Norway; 4Chair of Microsystems, , Technische Universität Dresden,, Dresden, Germany
The worldwide pandemic of obesity is associated with a substantial increase in the prevalence of metabolic-associated fatty liver disease and type 2 diabetes mellitus. Both conditions are metabolically interlinked and often coexist in patients, calling for reliable human in vitro models mimicking the interactions between pancreatic islets and the liver.
We recently developed a novel scalable pump-less recirculation OoC platform (rOoC) that generates a directional, gravity-driven flow and allows to link islets and liver organoids “on chip” without the need of external tubing. The dual rOoC iteration used in this study includes a membrane between two recirculation loops allowing directed transport of proteins from the islets to the liver compartment, while supporting the exchange of glucose and other small molecules between the circuits. It is therefore well suited to model and interrogate the inter-organ(oid) crosstalk.
The dual rOoC platform supported the long-term culture (for at least 2 weeks) of islet and liver organoids, evaluated by ATP content, concentrations of insulin and glucagon, albumin and urea. The co-culture of pluripotent stem cell (PSC)-derived islet and liver organoids in the dual-rOoC was beneficial for the functionality of both tissue representations, when compared to static and on-chip monocultures. An improved glucose-stimulated insulin secretion (GSIS) and insulin/glucose consumption by liver organoids demonstrated a successful crosstalk between islets and liver organoids in the dual-rOoC. Supplementation of culture medium with free fatty acids and fructose, mimicking an unhealthy diet, caused significant changes in the morphology, metabolism and functionality of both tissue representation alongside with increased levels of cytokines release, including IL6, CCL2, IL8, IL22.
In summary, we present a new scalable and easy-to-use pump-less OoC platform for the functional co-culture of islet and liver organoids, enabling the crosstalk between them, and suitable for disease modeling and drug discovery studies.
