02370nas a2200337 4500000000100000000000100001008004100002260001200043653003000055653001100085653003500096653002500131653001000156653001400166653001100180653001000191653002700201653002100228100001700249700001700266700001600283700001300299700001600312700001600328700001600344245012300360300001300483490000600496520151600502022001402018 2022 d c2022-0210aDiabetes Mellitus, Type 210aHumans10ainduced pluripotent stem cells10aIslets of Langerhans10aLiver10aorganoids10ahIPSCs10aLiver10amulti-organoid-on-chip10apancreatic islet1 aTingting Tao1 aPengwei Deng1 aYaqing Wang1 aXu Zhang1 aYaqiong Guo1 aWenwen Chen1 aJianhua Qin00aMicroengineered Multi-Organoid System from hiPSCs to Recapitulate Human Liver-Islet Axis in Normal and Type 2 Diabetes ae21034950 v93 aType 2 diabetes mellitus (T2DM) is a systematic multi-organ metabolic disease, which is characterized by the dynamic interplay among different organs. The increasing incidence of T2DM reflects an urgent need for the development of in vitro human-relevant models for disease study and drug therapy. Here, a new microfluidic multi-organoid system is developed that recapitulates the human liver-pancreatic islet axis in normal and disease states. The system contains two compartmentalized regions connected by a microchannel network, enabling 3D co-culture of human induced pluripotent stem cells (hiPSC)-derived liver and islet organoids for up to 30 days under circulatory perfusion conditions. The co-cultured liver and islet organoids exhibit favorable growth and improved tissue-specific functions. Transcriptional analyses reveal the activation of metabolically relevant signaling pathways in the co-cultured organoids. Notably, the co-culture system facilitates sensitive glucose-stimulated insulin secretion from islet organoids and increased glucose utilization in liver organoids by glucose tolerance tests. Both liver and islet organoids display mitochondrial dysfunction and decreased glucose transport capacity under high glucose conditions, which can be alleviated by metformin treatment. This novel multi-organoid system can recapitulate human-relevant liver-islet axis under both physiological and pathological conditions, providing a unique platform for future T2DM research and drug development. a2198-3844