HCN4 Charges Up the First Heart Field

Abstract

The concept of cardiac progenitors that persist late into heart development and potentially into postnatal life has ignited the interest of cardiac biologists. A little more than a decade ago, the prevailing notion of heart development centered on a cardiac tube containing immature cardiomyocytes that were committed to form specific segments of the mature heart.1 During the past 15 years, this textbook view was overturned by the modern rediscovery2-4 of the pioneering work of Viragh and Chalice5 and others, which showed that the heart tube grows by addition of new cardiomyocytes to the arterial and venous poles by differentiation of noncardiomyocyte progenitors. Thus, at the time that the initial heart tube is first visible in the developing embryo through heart looping and the initiation of septation, cardiac progenitors that are present at both poles of the heart differentiate into cardiomyocytes and thereby significantly contribute to heart growth (Figure A). Figure. Cardiac progenitor populations in the developing heart. A , Illustration of an E8.5 embryo highlighting the heart tube, containing differentiated cardiomyocytes and originating from the first heart field (FHF), and the second heart field (SHF), containing SHF progenitors. SHF progenitors differentiate into cardiac lineages to contribute to the ends of the heart tube (arrows). B , Lineage map of the developing heart. Around the time of gastrulation, a multipotent cardiac progenitor (likely Mesp1+) gives rise to Isl1+ SHF progenitors and possibly an FHF progenitor (yet to be identified). SHF progenitors yield most of the right ventricle (RV), outflow tract (OFT), atria, and sinoatrial node (SAN). FHF cardiomyocyte derivatives, arising from the hypothetical FHF progenitor or directly from Mesp1+ progenitors, express HCN4 at the cardiac crescent stage. These cells ultimately yield most of the left ventricle (LV) and portions of the atria and the cardiac …