The heart's rhythmic beat originates from the sinoatrial node, a tiny structure in the right atrium. It generates electrical impulses that spread through the heart, coordinating contractions of the atria and ventricles. When the sinoatrial node malfunctions, heartbeats can become dangerously slow or irregular, sometimes leading to fainting or more severe complications.

Understanding this system in humans has been challenging, as the sinoatrial node is tiny, hidden, and difficult to study directly. Besides, animal models only partially replicate the human heart's pacemaker features. To overcome these limitations, researchers started with human pluripotent stem cells and carefully guided their differentiation to mimic key developmental signals.

In a study published in Cell Stem Cell, a team led by Prof. ZENG An from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, along with Prof. LUO Zhe from Fudan University and Prof. DU Meirong from Tongji University, developed a lab-grown human heart organoid that mimics the body's natural pacemaker.

The researchers demonstrated how stem cells are guided to form three-dimensional (3D) "biological pacemaker" organoids capable of rhythmic beating. The organoids formed 3D structures containing pacemaker cells corresponding to the head, tail, and transitional regions of the natural sinoatrial node. They not only beat rhythmically on their own but also expressed genes similar to human embryonic pacemaker cells and responded to drugs known to modulate heart rate. When linked with atrial-like organoids, electrical signals propagated outward, modeling the basic conduction process from pacemaker to atrial tissue.

Moreover, the researchers explored whether these "biological pacemaker" organoids could model disease conditions. By introducing a mutation associated with familial slow heart rhythms, the organoids exhibited slower beating, reproducing key features of sinoatrial node dysfunction. Further experiments showed that a selective potassium channel blocker could partially restore normal rhythm, illustrating the model's potential for testing therapeutic interventions in a human context.

In the body, heart rate is further controlled by the nervous system, particularly parasympathetic nerves that slow the heartbeat. To model this, the researchers created cardiac plexus organoids enriched with parasympathetic-like neurons and connected them with pacemaker organoids. Nerve fibers extended toward the pacemaker cells, reducing their beating rate. Adding atrial-like organoids to form a three-component "nerve–sinoatrial node–atrium" assembloid showed that neural regulation could propagate to downstream tissue, mimicking how the nervous system fine-tunes heart rhythm in vivo.

Finally, the researchers investigated how neural signals contribute to pacemaker maturation. Spatial transcriptomic analysis revealed that pacemaker cells expressed the receptor GPR37, while neighboring neurons produced its ligand PSAP. Experiments demonstrated that PSAP signaled through GPR37 to promote pacemaker cell maturation, and disrupting this signaling impaired maturation, while supplementing PSAP restored it, suggesting a key role for the nervous system in developing human pacemaker cells.

This human-based in vitro system offers a new way to study heart rhythm formation, pacemaker maturation, inherited heart rhythm disorders, and drug responses. The study lays a foundation for the exploration of biological pacemakers and other cardiac therapies, providing a versatile and human-relevant platform for both basic research and clinical applications.