A novel microphysiological system successfully integrated hiPSC-derived cardiomyocytes and sympathetic neurons, demonstrating functional neuro-cardiac interactions responsive to nicotine and propranolol.
A novel hiPSC-based microphysiological system successfully models functional sympathetic neuro-cardiac interactions, providing a platform for disease modeling and pharmacological screening.
The cardiac autonomic nervous system is a key driver of various cardiac disorders and arrhythmias. However, investigating neuronal regulation of the human heart has proven difficult due to immitted and reliable experimental models. Here, we present a novel microphysiological system utilizing a compartmentalized microfluidic device (MFD) to integrate co-cultured human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs) and sympathetic neurons (hiPSC-SNs). MFD is composed of two wide-open chambers separated by microfluidic microchannels. hiPSC-SNs were characterized by confocal imaging and RT-qPCR for the expression of peripherin, tyrosine hydroxylase, and β-tubulin III, as well as high levels of dopamine β-hydroxylase and nicotinic acetylcholine receptors. Furthermore, patch-clamp techniques confirmed their functional maturity, showing spontaneous action potentials and positive responses to nicotine (1µM). Co-culturing hiPSC-CMs and hiPSC-SNs within the MFD facilitated axonal projection into the cardiomyocyte chamber, establishing a physical connection between the two cell types. After 10 days of co-culture, functional integration was confirmed by a significant increase in the action potential frequency and beating rate of hiPSC-CMs, as recorded by patch-clamp and video motion tracking, respectively. Notably, nicotine application in the neuronal chamber accelerated these rates in hiPSC-CMs chamber, whereas the administration of the β-blocker, propranolol (5µM), effectively decreased the beating rates. Collectively, these data demonstrate the feasibility of differentiating hiPSCs into functional sympathetic neurons and establishing a robust neuro-cardiac interface. This microphysiological system represents a powerful platform for investigating disorders characterized by impaired neuro-cardiac interactions, offering a valuable tool for both disease modeling and pharmacological screening.
Reisqs et al. (2026) studied cardiac disorders and arrhythmias. hiPSC-based microphysiological system (co-culture of hiPSC-CMs and hiPSC-SNs) was evaluated on functional integration (action potential frequency and beating rate). A novel microphysiological system successfully integrated hiPSC-derived cardiomyocytes and sympathetic neurons, demonstrating functional neuro-cardiac interactions responsive to nicotine and propranolol.