Developmental Origin of the Cardiac Conduction System: Insight from Lineage Tracing

Abstract

The components of the cardiac conduction system (CCS) generate and propagate the electrical impulse that initiates cardiac contraction. These interconnected components share properties, such as automaticity, that set them apart from the working myocardium of the atria and ventricles. A variety of tools and approaches have been used to define the CCS lineages. These include genetic labeling of cells expressing lineage markers and fate mapping of dye labeled cells, which we will discuss in this review. We conclude that there is not a single CCS lineage, but instead early cell fate decisions segregate the lineages of the CCS components while they remain interconnected. The latter is relevant for development of therapies for conduction system disease that focus on reprogramming cardiomyocytes or instruction of pluripotent stem cells.

Does cardiac development provide heart research with novel therapeutic approaches?

“…Retrospective clonal analyses showed that the nlacz gene transmitted cells are organized into clusters of clonally related cardiomyocytes, which are composed of a mixture of both working and specialized conductive cardiomyocytes 68 . These nlacz clusters were found in all conductive system compartments, except in the SAN, indicating a common origin between the specialized conductive cardiomyocytes and their neighbor working cardiomyocytes 66 , 68 , 69 . Of note, this retrospective clonal analysis does not exclude the contribution of other progenitor populations to the conductive system 69 .…”

“…Irrespective of the origin, the coronary vasculature is essential for the subsequent heart morphogenesis and embryonic viability such that deficient coronary development impairs myocardium compaction and leads to embryonic lethality 28 , 65 ( Figure 1A, B ). The cardiac conduction system is composed of specialized cardiomyocytes that assemble into a complex and heterogeneous structure to make up a central conduction system located in the atria (sinoatrial node [SAN], atrioventricular ring bundles, and the atrioventricular node) and a peripheral conduction system in the ventricles (left and right branches of His bundle, LBB and RBB, and left and right peripheral conductive system or the Purkinje fibers) 66 . SAN cardiomyocytes derive from the posterior SHF; however, lineage analyses revealed an early lineage segregation from the atrial working cardiomyocyte progenitors 66 , 67 .…”

“…The cardiac conduction system is composed of specialized cardiomyocytes that assemble into a complex and heterogeneous structure to make up a central conduction system located in the atria (sinoatrial node [SAN], atrioventricular ring bundles, and the atrioventricular node) and a peripheral conduction system in the ventricles (left and right branches of His bundle, LBB and RBB, and left and right peripheral conductive system or the Purkinje fibers) 66 . SAN cardiomyocytes derive from the posterior SHF; however, lineage analyses revealed an early lineage segregation from the atrial working cardiomyocyte progenitors 66 , 67 . Retrospective clonal analyses showed that the nlacz gene transmitted cells are organized into clusters of clonally related cardiomyocytes, which are composed of a mixture of both working and specialized conductive cardiomyocytes 68 .…”

“…Of note, this retrospective clonal analysis does not exclude the contribution of other progenitor populations to the conductive system 69 . Additionally, other cardiovascular progenitors—that is, PEO (EPDCs) 70 and cNCCs 71 —have been suggested to contribute to the development of the conductive system; however, this participation remains controversial 66 , 69 , 72 ( Figures 1A, 1B ).…”

NOTCH1 is critical for fibroblast-mediated induction of cardiomyocyte specialization into ventricular conduction system-like cells in vitro

“…Cardiac fibroblasts are present throughout the myocardium and are enriched in the microenvironment surrounding the ventricular conduction system (VCS) 4 – 6 . The VCS is a specialized structure responsible for conduction of electrical potentials throughout the ventricles 7 , 8 . The VCS initiates in the His bundle and extends to the peripheral ventricular conduction system (PVCS) composed of rapidly conducting fibers, known as Purkinje fibers 9 .…”