Abstract 1122: The Mammalian Heart Contains Vascular and Myocyte Niches
During development the myocyte compartment and the coronary vasculature are generated from distinct progenitor cell classes which are activated at different stages of embryonic life. To determine whether the adult heart is similarly regulated by a coronary vascular progenitor cell (VPC) and a myocyte progenitor cell (MPC), the presence of vascular and myocyte niches was established in the mouse, rat, dog and human heart. Typically, VPCs are c-kit-positive and flk1/KDR positive while MPCs are c-kit-positive but flk1/KDR negative. These phenotypic properties were employed to identify vascular niches within the coronary circulation and myocyte niches in the myocardial interstitium. By definition, vascular and myocyte niches have to be composed of progenitor cells structurally and functionally connected to supporting cells, which modulate growth signals involved in the preservation of stemness and activation of cell differentiation. In the heart of rodents, dogs and humans, flk1/KDR positive VPCs were detected in large, intermediate and small-sized arteries and arterioles and capillary network. Flk1/KDR positive VPCs expressed connexin 43 and N-cadherin and these junctional proteins were distributed between VPCs and endothelial cells (ECs) and smooth muscle cells (SMCs). ECs and SMCs may represent the supporting cells of coronary vascular niches. Importantly, flk1/KDR positive VPCs showed at times vWF and CD31 or TGF-β1 receptors providing a linear relationship between these primitive cells and ECs and SMCs, respectively. Similarly, clusters of flk1/KDR negative-MPCs were found; MPCs were intimately connected by gap and adherens junctions to myocytes and fibroblasts. In the niches, MPCs divided symmetrically and asymmetrically as demonstrated by the uniform and non-uniform distribution of the cell fate determinants Numb and α-adaptin. The localization of these proteins at one pole of a dividing MPC resulted in the generation of a stem cell and a myocyte committed cell. In vitro, both VPCs and MPCs formed multicellular clones. However, VPCs acquired mostly the EC and SMC lineages, and MPCs generated predominantly a myocyte progeny. Thus, the turnover of myocytes and coronary vessels is controlled by two distinct populations of primitive cells.