Development and modeling of cardiac autonomic innervation

Autonomic innervation is important for heart development and function, as well as for the response to injury and hemodynamic stress. However, the mechanisms underlying neurocardiac interactions are difficult to investigate in vivo, prompting the need for advanced engineering of in vitro models of innervated cardiac tissues. Here, we review the embryonic development of the heart and postganglionic autonomic neurons and discuss the functional consequences of cardiac autonomic innervation, focusing on its trophic roles in neonatal and adult hearts. We highlight methods for generating functional cardiomyocytes and autonomic neurons from human pluripotent stem cells and discuss the benefits and limitations of existing in vivo and in vitro cardiac innervation models. Lastly, we present a roadmap for the development of high-fidelity, mature pluripotent stem cell-derived models of cardiac autonomic innervation to address outstanding questions in the field.