Human PSC-derived sinoatrial node-cardiac plexus assembloids model innervation-associated maturation of pacemaker systems

  • Cell Stem Cell. 2026 Jun 4;33(6):945-963.e11. doi: 10.1016/j.stem.2026.04.018.
Tongdong Zhang  1 ,  Lei Fan  1 ,  Feibai Yao  2 ,  Ge Li  3 ,  Guotong Lin  4 ,  Yi Yang  1 ,  Fenglin Qian  1 ,  Chencheng Liu  1 ,  Qi Tang  1 ,  Wendi Wang  5 ,  Chunfang Xu  6 ,  Xiaoliang Xu  1 ,  Yu Chang  7 ,  Wen Yang  8 ,  Jiangdong Gong  8 ,  Yutong Wang  1 ,  Shichao Huang  1 ,  Renchu Guan  5 ,  Lin Lin  1 ,  Qing Jing  9 ,  Zhaohua Yang  10 ,  Tingrui Pan  8 ,  Xin Cheng  1 ,  Lei Song  4 ,  Meirong Du  11 ,  Zhe Luo  12 ,  An Zeng  13
Affiliations
  • 1. Key Laboratory of Multi-cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 2. Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai 200031, China.
  • 3. National Institute of Biological Sciences, Beijing, China; Peking University, Tsinghua University, National Institute of Biological Sciences Joint Graduate Program, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 4. Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200125, China.
  • 5. Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, College of Software, Jilin University, Changchun 130012, Jilin, China.
  • 6. Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China.
  • 7. Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology, Shenzhen 518107, China.
  • 8. Center for Intelligent Medical Equipment and Devices, Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou 215123, Jiangsu, China.
  • 9. Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 10. Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200031, China.
  • 11. Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China. Electronic address: [email protected].
  • 12. Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai 200031, China. Electronic address: [email protected].
  • 13. Key Laboratory of Multi-cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected].
PMID: 42143017 DOI: 10.1016/j.stem.2026.04.018
Abstract

Heart rhythm and contraction are initiated by electrical impulses generated by the sinoatrial node (SAN) and modulated by intrinsic cardiac neural inputs. Despite its physiological importance, human in vitro systems that recapitulate neural-SAN interactions are lacking. Here, we develop SAN-plexus assembloids by integrating human pluripotent stem cell-derived SAN organoids (SANOs) with cardiac ganglionated plexus organoids (CGPOs), together with atrial-like cardiac organoids, to model pacemaker-to-atrial conduction in a tri-assembloid system. This platform exhibits molecular, structural, and electrophysiological features of human pacemaker activity and enables functional interrogation of neural control over SAN automaticity, including disease-associated conduction dysfunction. By integrating spatial transcriptomics of human SAN tissue with assembloid-based functional analyses, we identify a neuron-to-pacemaker signaling program in which CGPO-derived prosaposin engages the SAN-enriched receptor GPR37 to promote pacemaker maturation. Together, this work establishes SAN-plexus assembloids as a human platform for studying intrinsic neuro-cardiac interactions in pacemaker development and disease.

Keywords
PSAP-GPR37 signaling; PSC-derived cardiomyocytes; SAN organoids; cardiac plexus organoids; congenital SAN dysfunction; electrophysiology; neuro-cardiac crosstalk; pacemaker maturation; sinoatrial node; spatial transcriptomics.
Products
Inhibitors & Agonists
Other Products