Multi-tissue microphysiological system captures integrated responses to nutritional overload and metabolic therapy

This study used a human six-tissue microphysiological system to examine how shared multi-tissue interaction, graded nutrient exposure, and pharmacologic perturbation shape tissue-specific transcriptional programs relevant to systemic glucose regulation. The MOTIVE-6 platform integrated hiPSC-derived midbrain organoids, intestinal epithelium, liver organoids, pancreatic islets, visceral adipocytes, and skeletal muscle in a shared circulating media environment. Bulk RNA-seq was performed on individual tissue compartments after four days of culture under Low, Mid, or High nutrient conditions, with additional High-nutrient conditions treated with metformin or semaglutide. Matched isolation cultures were used to distinguish transcriptional effects associated with multi-tissue interaction from those observed in independently cultured tissues. This dataset enables analysis of tissue-specific responses to inter-tissue signaling, nutrient state, and anti-diabetic drug exposure in a perfused human multi-tissue model.