Bioengineering of a human innervated cardiac muscle model
Cardiac autonomic neurons control cardiac contractility. Dysregulation of the autonomic nervous system can lead to sympathetic overdrive resulting in heart failure and an increased incidence of fatal arrhythmias. Here, we introduce innervated engineered human myocardium (iEHM), a novel model of neuro-cardiac junctions, constructed by fusion of a bioengineered neural organoid patterned to autonomic nervous system (SNO) and engineered human myocardium (EHM). Projections of sympathetic neurons into EHM formed presynaptic terminals in close proximity to cardiomyocytes and the extensive vascular network co-developing in the tissues. Contractile responses to optogenetic stimulation of the accordingly engineered neuronal component demonstrated functionality of the engineered neuro-cardiac junctions. Modeling long-QT 2 related to KCNH2 mutations in iEHM revealed early afterdepolarizations and autonomic neuron hyperactivity, suggesting a contribution of the autonomic nervous system to hERG-channel dysfunction-related arrhythmias. Collectively, our data demonstrate the utility of iEHM in the delineation of neuron-cardiomyocyte crosstalk at the tissue level and may serve as an important step towards the engineering a human brain-to-heart axis in a dish.
Cardiac autonomic neurons control cardiac contractility. Dysregulation of the autonomic nervous system can lead to sympathetic overdrive resulting in heart failure and an increased incidence of fatal arrhythmias. Here, we introduce innervated engineered human myocardium (iEHM), a novel model of neuro-cardiac junctions, constructed by fusion of a bioengineered neural organoid patterned to autonomic nervous system (SNO) and engineered human myocardium (EHM). Projections of sympathetic neurons into EHM formed presynaptic terminals in close proximity to cardiomyocytes and the extensive vascular network co-developing in the tissues. Contractile responses to optogenetic stimulation of the accordingly engineered neuronal component demonstrated functionality of the engineered neuro-cardiac junctions. Modeling long-QT 2 related to KCNH2 mutations in iEHM revealed early afterdepolarizations and autonomic neuron hyperactivity, suggesting a contribution of the autonomic nervous system to hERG-channel dysfunction-related arrhythmias. Collectively, our data demonstrate the utility of iEHM in the delineation of neuron-cardiomyocyte crosstalk at the tissue level and may serve as an important step towards the engineering a human brain-to-heart axis in a dish.
European Bioinformatics Institute