Human PSC-derived organoids model sympathetic ganglion development and its functional crosstalk with the heart.

The sympathetic ganglia are essential components of the nervous system that regulate various aspects of involuntary body functions. Recapitulating sympathetic ganglion development with three-dimensional (3D) organoids is challenging and has not been achieved. Here, we report a method to differentiate human pluripotent stem cells into 3D neural organoids that resemble peripheral sympathetic ganglia, producing both neurons and glial cells of the ganglia in a self-organized manner. We developed an organoid system to construct functional connections between the sympathetic ganglia and one of their peripheral targets, the heart, by fusing human sympathetic ganglion organoids (hSGOs) and heart-forming organoids. Notably, this system enables the evaluation of signaling controls (i.e., nerve growth factor [NGF] signaling) on human sympathetic-to-cardiac innervation and reveals the reciprocal impacts between the sympathetic and cardiac lineages during their co-development. Our study provides a physiologically relevant platform for understanding the development of human sympathetic ganglia, their crosstalk with peripheral targets, and related diseases.