Dynamic Cellular Integration Drives Functional Assembly of the Heart’s Pacemaker Complex

Abstract

Summary: Impulses generated by a multicellular, bioelectric signaling center termed the sinoatrial node (SAN) stimulate the rhythmic contraction of the heart. The SAN consists of a network of electrochemically oscillating pacemaker cells encased in a heterogeneous connective tissue microenvironment. Although the cellular composition of the SAN has been a point of interest for more than a century, the biological processes that drive the tissue-level assembly of the cells within the SAN are unknown. Here, we demonstrate that the SAN’s structural features result from a developmental process during which mesenchymal cells derived from a multipotent progenitor structure, the proepicardium, integrate with and surround pacemaker myocardium. This process actively remodels the forming SAN and is necessary for sustained electrogenic signal generation and propagation. Collectively, these findings provide experimental evidence for how the microenvironmental architecture of the SAN is patterned and demonstrate that proper cellular arrangement is critical for cardiac pacemaker biorhythmicity. : How the higher order, tissue-level architecture of the heart’s pacemaker region is patterned during development is poorly understood. Bressan et al. demonstrate that a cellular remodeling process, which depends on the integration of pacemaker muscle with proepicardial-derived mesenchymal cells, establishes the microenvironmental conditions required for rhythmic stimulation of the heart. Keywords: sinoatrial node, cardiac pacemaker cell, cardiac morphogenesis, proepicardium