BRAIN-LIKE CYTOARCHITECTURE AND FUNCTION OF THE HEARTS SINOATRIAL NODE

National Institute On Aging

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Abstract

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 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) and a novel S100B+/GFAP- interstitial cell population, with unique morphology and distinct distribution pattern, creating complex interactions with other cell types in the node, particularly with HCN4 expressing cells. TEM identified a similar population of interstitial cells as telocytes, which appeared to secrete vesicles towards pacemaker cells. Application of S100B to SAN preparations desynchronized Ca 2+ signaling in HCN4 expressing cells, and increased variability in SAN impulse rate and rhythm. Conclusions: We discovered a novel S100B+/GFAP- interstitial cell type resembling telocytes in TEM images. S100B was found to desynchronize Ca 2+ signaling in HCN4 expressing cells, and to increase variability in SAN impulse rate and rhythm. The autonomic plexus, peripheral glial cell web, and a novel S100B+/GFAP- interstitial cell type embedded within the HCN4+ cell meshwork increases structural and functional complexity of the sinoatrial node and provides a new regulatory pathway of rhythmogenesis.