The Heart’s Pacemaker Mimics Brain Cytoarchitecture and Function

Abstract Objectives This study sought to describe the 3D cytoarchitecture of sinoatrial node tissue, including autonomic innervation, peripheral glial cells, and pacemaker cells. Background The sinoatrial node of the heart produces rhythmic action potentials (AP), generated via calcium signaling within and among pacemaker cells. Our previous work has described the SAN as composed of an HCN4-expressing pacemaker cell meshwork, which merges with a network of CX43+/F-actin+ cells. It is also known that sympathetic and parasympathetic innervation from epicardial ganglia create an autonomic plexus in the sinoatrial node, which modulates heart rate and rhythm. However, the anatomical details of the interaction of this plexus with the pacemaker cell meshwork have yet to be described. Methods 3D confocal laser-scanning microscopy of triple immunolabeled SAN whole mount preparations with combinations of antibodies for HCN4, S100B, GFAP, ChAT or VAChT, and TH, and transmission electron microscopy (TEM). Results The SAN exhibited heterogeneous autonomic innervation, which was accompanied by a web of peripheral glial cells (PGCs). Further, we identified a novel S100B+/GFAP- interstitial cell population, with unique morphology and distinct distribution pattern, creating complex interactions with other cell types in the node. TEM images showed a similar population of cells, here identified as telocytes, which appeared to secrete vesicles towards pacemaker cells. Application of S100B protein to SAN preparations induced distinct changes in rhythmogenic calcium signaling. Conclusions The autonomic plexus and its associated peripheral glial cell web, a novel network of S100B expressing interstitial cells resembling telocytes, and a meshwork of HCN4+ cells interact to impart structural complexity to the sinoatrial node. Summary Table