Novel Insights into the Sinoatrial Node in Single-Cell RNA Sequencing: From Developmental Biology to Physiological Function

Normal cardiac automaticity is dependent on the pacemaker cells of the sinoatrial node (SAN). Insufficient cardiac pacemaking leads to the development of sick sinus syndrome (SSS). Since currently available pharmaceutical drugs and implantable pacemakers are only partially effective in managing SSS, there is a critical need for developing targeted mechanism-based therapies to treat SSS. SAN-like pacemaker cells (SANLPCs) are difficult to regenerate in vivo or in vitro because the genes and signaling pathways that regulate SAN development and function have not been fully elucidated. The development of more effective treatments for SSS, including biological pacemakers, requires further understanding of these genes and signaling pathways. Compared with genetic models and bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq) technology promises to advance our understanding of cellular phenotype heterogeneity and molecular regulation during SAN development. This review outlines the key transcriptional networks that control the structure, development, and function of the SAN, with particular attention to SAN markers and signaling pathways detected via scRNA-seq. This review offers insights into the process and transcriptional network of SAN morphogenesis at a single-cell level and discusses current challenges and potential future directions for generating SANLPCs for biological pacemakers.