Development of a vascularized multi-organoid-on-a-chip to model the heart-islet axis in diabetic cardiomyopathy.

Abstract

The dynamic crosstalk between pancreatic islets and the heart plays a critical yet poorly understood role in diabetic cardiomyopathy (DCM). Here, we present a vascularized multi-organoid-on-a-chip platform that enables the perfusion co-culture of human iPSC-derived vascularized cardiac organoids (VCOs) and vascularized islet organoids (VIOs). Under a gradient of hyperglycemic stress, this system recapitulated key features of DCM, including cardiomyocyte structural disassembly and vascular dysfunction. Crucially, co-culture with functional VIOs provided substantial protection against hyperglycemia, mitigating cardiac damage by restoring metabolic and contractile gene programs. Our study establishes a modular and physiologically relevant model to dissect the dose-dependent protective role of islets in diabetic heart disease and to screen for interventions targeting inter-organ communication.