IT之家 May 17 news - Every heartbeat begins in a tiny yet crucial structure in the right atrium: the sinoatrial node. This "commander-in-chief" of the heart, under the precise regulation of the nervous system, continuously emits electrical impulses that direct the atria and ventricles to contract and pump blood in coordination.

When the sinoatrial node malfunctions, the heartbeat may slow or even stop, posing a life-threatening risk in severe cases. However, the human sinoatrial node is extremely small, deeply located, and human tissue samples are exceptionally hard to obtain; animal models such as mice cannot accurately replicate human heartbeats or the neural regulation of heart rhythm. How to create a realistic human "biological pacemaker" in the laboratory has long been a major challenge in the field of cardiac pacing and conduction research.

A research team from the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, has achieved a key breakthrough in this challenge. The group led by Zeng An, in collaboration with colleagues, successfully constructed a human "biological pacemaker" - a sinoatrial node organoid - from human pluripotent stem cells in a dish, and connected it with a cardiac plexus organoid to realize neural regulation of the heartbeat. The findings were published on May 15 in *Cell Stem Cell*.

The research team systematically screened key signaling pathways involved in embryonic development and successfully guided the differentiation of human pluripotent stem cells into sinoatrial node organoids with three-dimensional structure.

This artificial organoid is not simply a collection of cells; rather, it contains three cell subtypes highly corresponding to the pacemaker cells of the human sinoatrial node, capable of autonomously generating stable and rhythmic beating. When this organoid was connected to an atrial-like organoid, electrical signals could be smoothly initiated from the sinoatrial node side and conducted to the atrial-like tissue, successfully simulating for the first time the entire process from “pacing” to “conduction” in the heart in vitro. Further transcriptomic analysis revealed that these organoids closely resemble human embryonic sinoatrial node cells in gene expression signatures and can respond to various drugs that modulate heart rate.

To explore the disease modeling value of this system, the team used gene editing technology to introduce the KCNJ3 c.247A mutation associated with familial bradyarrhythmia into the sinoatrial node organoids. >C mutation. The results showed that the beating frequency of the mutated organoids was significantly reduced, successfully recapitulating the key phenotype of human sinus node dysfunction. More importantly, subsequent experiments revealed that the potassium channel-selective blocker Tertiapin-Q could effectively improve this abnormal rhythm. These findings indicate that this humanized model can not only be used to deeply analyze the mechanisms underlying inherited arrhythmias, but also serve as a novel in vitro platform for the evaluation and screening of potential therapeutic drugs.

In the real human body, the sinoatrial node does not work in isolation. The cardiac autonomic nervous system, like a "tuner," adjusts heart rate in real time through the vagus and sympathetic nerves according to the body's movement, rest, and emotional states. The parasympathetic component of the vagus nerve is primarily responsible for lowering heart rate. To replicate this complex regulatory process in vitro, the research team further constructed cardiac ganglionated plexus organoids enriched with parasympathetic neurons and assembled them with sinoatrial node organoids. Experimental results showed that nerve fibers extending from the cardiac ganglionated plexus organoids actively projected toward the sinoatrial node organoids, forming functional connections and successfully reducing the spontaneous beating rate of the sinoatrial node organoids. Subsequently, the team went a step further by integrating atrial-like organoids into the model, building a three-organoid assembly model of "nerve—sinoatrial node—atrium." The study found that the regulatory signals from the nerves not only acted on the pacemaker itself but were also transmitted stepwise to the downstream atrial tissue, leading to a coordinated slowing of atrial rhythm, thus successfully simulating the fine regulatory process of the nervous system on the cardiac pacing system in the body.

On this basis, the research team combined spatial transcriptomic analysis of the sinoatrial node region in human embryonic hearts to construct a high-precision molecular map of the human sinoatrial node and its surrounding neural microenvironment. They discovered that a receptor called GPR37 is specifically enriched in human sinoatrial node pacemaker cells, while its ligand PSAP mainly originates from adjacent neurons. Subsequent organoid experiments confirmed that this regulatory axis plays a key role—PSAP secreted by neurons acts like a precise "key" on the GPR37 receptor on the surface of pacemaker cells, driving them from an initial state toward full maturation. This means that the team's findings not only reconstruct the dynamic process of real-time heart rate regulation but also reveal for the first time the intrinsic molecular mechanism through which the nervous system promotes the maturation of the human cardiac pacemaker system at the long-term developmental level.

The study successfully reconstructed key functions and neural regulation processes of the human heart's natural pacemaker system in vitro, providing a humanized, highly controllable experimental platform for arrhythmia research, drug screening, and future development of biological pacemakers. The publication of this achievement marks an important step forward in scientists' understanding and treatment of arrhythmia-related diseases.

IT之家附论文地址：
https://www.cell.com/cell-stem-cell/abstract/S1934-5909(26)00158-X

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