Key result
hiPSC-derived parasympathetic neurons reach mature resting potentials of ~-65 mV and functionally modulate atrial cardiomyocytes.
Why the study?
Peripheral parasympathetic ganglia lie adjacent to their target organs and their dysfunction contributes to diseases like atrial fibrillation, but they have challenging accessibility for primary culture.
This protocol provides an accessible, scalable human iPSC-derived parasympathetic neuron and atrial cardiomyocyte co-culture platform to study autonomic neuromodulation, atrial fibrillation disease modeling, and drug discovery.
Answers are grounded in this paper and cite their sources.
Offers scalable hiPSC co-culture for autonomic neuromodulation assays; leaves open translation to AF modeling and therapies.
Summary Peripheral parasympathetic ganglia lie adjacent to their target organs; their dysfunction contributes to diseases like atrial fibrillation. Due to their challenging accessibility for primary culture, we provide a step-by-step protocol to generate parasympathetic neurons from human induced pluripotent stem cells (hiPSC). They reproduce numerous native physiological features: cholinergic and autonomic markers, functional nicotinic receptors and electrophysiological properties. We also describe a co-culture system with hiPSC-atrial cardiomyocytes allowing neuromodulation of cardiomyocyte activity and offering a platform for drug discovery and disease modelling. Highlights Steps to generate parasympathetic neurons from human induced pluripotent stem cells Guidance of the functional assessment of the neurons (whole-cell patch clamp and Ca 2+ imaging) Instructions on how to co-culture these neurons with hiPSC-derived atrial cardiomyocytes Guidance of the functional assessment of the neuronal modulation of cardiomyocyte activity Graphical abstract
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Thomas et al. (2026) studied Parasympathetic neuron and atrial cardiomyocyte co-culture modeling. Step-by-step differentiation of hiPSCs into parasympathetic neurons and co-culture with hiPSC-atrial cardiomyocytes with nicotine application vs. Monoculture of hiPSC-atrial cardiomyocytes, ventricular-like differentiation without retinoic acid, or baseline pre-nicotine state was evaluated on Electrophysiological maturation (resting membrane potential) and functional neuromodulation of spontaneous Ca2+ transients in co-cultured hiPSC-atrial cardiomyocytes. hiPSC-derived parasympathetic neurons achieved an average resting membrane potential of -65 mV from day 39 and reduced spontaneous Ca2+ transients in co-cultured atrial cardiomyocytes upon nicotine application.
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