Studying the pathophysiologic connection between cardiovascular and nervous systems using stem cells.

The cardiovascular and nervous systems are deeply connected during development, health, and disease. Both systems affect and regulate the development of each other during embryogenesis and the early postnatal period. Specialized neural crest cells contribute to cardiac structures, and a number of growth factors released from the cardiac tissue (e.g., glial cell line-derived neurotrophic factor, neurturin, nerve growth factor, Neurotrophin-3) ensure proper maturation of the incoming parasympathetic and sympathetic neurons. Physiologically, the cardiovascular and nervous systems operate in harmony to adapt to various physical and emotional conditions to maintain homeostasis through sympathetic and parasympathetic nervous systems. Moreover, neurocardiac regulation involves a neuroaxis consisting of cortex, amygdala, and other subcortical structures, which have the ability to modify lower-level neurons in the hierarchy. Given the interconnectivity of cardiac and neural systems, when one undergoes pathological changes, the other is affected to a certain extent. In addition, there are specific neurocardiac diseases that affect both systems simultaneously, such as Huntington disease, Lewy body diseases, Friedreich ataxia, congenital heart diseases, Danon disease, and Timothy syndrome. Over the last decade, in vitro modeling of neurocardiac diseases using induced pluripotent stem cells (iPSCs) has provided an invaluable opportunity to elevate our knowledge about the brain-heart connection, since previously primary cardiomyocytes and neurons had been extremely difficult to maintain long-term in vitro. Ultimately, the ability of iPSC technology to model abnormal functional phenotypes of human neurocardiac disorders, combined with the ease of therapeutic screening using this approach, will transform patient care through personalized medicine in the future.