Engineering a multi-organ chip to explore heart-brain crosstalk in health and pathology

Background The heart and brain are tightly interconnected through autonomic innervation, orchestrating cardiovascular function via sympathetic and parasympathetic signaling. Dysregulation of this axis contributes to multi-organ pathologies, including stroke, arrhythmias, and cardiometabolic complications. Mechanistic insights into this brain–heart axis remain limited because current in vitro approaches, which are typically more simple cardiac–nerve co-cultures, lack brain components and compartmentalization, leaving this complex interaction largely confined to in vivo studies. Methods and Results We developed a human pluripotent stem cell-derived heart–brain-on-chip model using advanced organ-on-chip technology. The platform enables compartmentalized co-culture of engineered brain, cardiac tissue, and autonomic nerves (parasympathetic and sympathetic). Microfluidic channels support neurite outgrowth and direct innervation of both cardiac and brain compartments. Parasympathetic-like tissues express cholinergic markers, and cardiac tissue responds to acetylcholine, demonstrating functional autonomic regulation on-chip. Conclusion This heart–brain-on-chip provides a novel platform to study cardiac innervation, autonomic regulation, and multi-organ communication, offering new opportunities for modeling cardiovascular and neurological disorders.