https://www.cas.cn/syky/202605/t20260527_5111039.shtml
https://www.cell.com/cell-stem-cell/abstract/S1934-5909(26)00158-X
The heart’s ability to beat continuously and rhythmically relies on a “natural pacemaker” located in the right atrium—the sinoatrial (SA) node. Acting as the heart’s “central commander,” it continuously generates electrical signals under the regulation of the nervous system; these signals then travel through the cardiac conduction system, directing the atria and ventric to contract in coordination and pump blood. Should this “central commander” malfunction, the heartbeat may slow down or even pause—a condition that, in severe cases, can be life-threatening.
Researchers from the CAS Center for Excellence in Molecular Cell Science have constructed the first human-derived “biological pacemaker” in a petri dish: an SA node organoid derived from human pluripotent stem cells. By subsequently connecting this organoid to a cardiac plexus organoid, the team demonstrated the neural regulation of cardiac rhythm.
By mimicking key signaling pathways involved in embryonic development and conducting systematic screening, the research team guided stem cells to differentiate into three-dimensional SA node organoids capable of autonomously generating stable heartbeats. When connected to atrial-like organoids, these structures allowed electrical signals to originate from the SA node side and propagate into the atrial tissue, thereby successfully simulating the physiological “pacing-conduction” process observed *in vivo*.
Leveraging this model, the team introduced genetic mutations associated with familial SA node dysfunction into the organoids. They observed that the beating rate of these “pacemakers” slowed significantly, thereby faithfully recapitulating the key characteristics of bradyarrhythmia (slow heart rhythm disorders). Notably, upon pharmacological treatment, the abnormal rhythms showed improvement; this finding suggests that the model not only aids in elucidating the underlying mechanisms of heart-rate-related diseases but also serves as a valuable tool for evaluating potential therapeutic drugs.
Within the context of a real human heart, the SA node does not operate in isolation; rather, the surrounding nerves act as “tuners,” constantly adjusting the heart rate in response to the body’s physiological state. To simulate this process, the team constructed neuron-rich cardiac plexus organoids and assembled them with sinoatrial node (SAN) organoids and atrial organoids. Experiments demonstrated that nerve fibers could extend into the SAN organoids, regulating their beating frequency and transmitting electrical signals to the downstream atrial tissue. Furthermore, by integrating a spatial atlas of the human embryonic SAN with in vitro intervention experiments, the study revealed that neural pathways specifically enriched in humans not only regulate heart rhythm but also promote the maturation of the cardiac pacing system: the multifunctional glycoprotein PSAP—secreted by neurons—acts like a “key,” binding to the receptor molecule GPR37 on the surface of pacemaker cells to facilitate their progression toward a mature state.