Developmental origin and lineage plasticity of endogenous cardiac stem cells

Abstract

Over the past two decades, several populations of cardiac stem cells have been described in the adult mammalian heart. For the most part, however, their lineage origins and in vivo functions remain largely unexplored. This Review summarizes what is known about different populations of embryonic and adult cardiac stem cells, including KIT(+), PDGFRα(+), ISL1(+)and SCA1(+)cells, side population cells, cardiospheres and epicardial cells. We discuss their developmental origins and defining characteristics, and consider their possible contribution to heart organogenesis and regeneration. We also summarize the origin and plasticity of cardiac fibroblasts and circulating endothelial progenitor cells, and consider what role these cells have in contributing to cardiac repair.

Keywords: Adult mammalian heart; Cardiac stem cells; Cardiovascular cells; Embryonic precursor cells; Heart organogenesis; Regeneration.

Fig. 1.

The adult mammalian heart. The adult mammalian heart is made up of four chambers: the right and left ventricles (RV and LV) and right and left atria (RA and LA). The ventricles are separated by the interventricular septum (IS). The vena cava and the aorta carry the flow of blood to and from the heart, respectively. Blood low in oxygen (blue arrows) from the different tissues is collected into the right atrium via the superior and inferior vena cava and flows to the lungs through the right ventricle. Oxygenated blood (red arrows) from the lungs flows into the left atrium and is pumped into the aorta by the left ventricle. This system allows oxygenated and non-oxygenated blood to be completely separate. Figure created using Servier medical art.

Fig. 2.

Lineage contributions to the forming heart. (A-D) During gastrulation at E6.5-E7.0 (A,B), mesodermal and endodermal cells corresponding to distinct organ territories, including heart progenitors from the first heart field (FHF, red) and second heart field (SHF, green), undergo lateral migration (arrows) away from the primitive streak (thick black line). At the cardiac crescent stage at E7.5 (C) and during the formation of the early heart tube at E8.0 (D), FHF and SHF descendants are shown in red and green, respectively. Solid arrows indicate ongoing rearrangement of FHF and SHF cells from the cardiac crescent as FHF cells form the primary heart tube, with SHF cells being added to the poles of the primary heart tube (D). (E) Frontal and lateral views of the heart region at E9.0 showing looped heart tube. Dashed arrows indicate migration of cardiac neural crest cells to the heart. (F,G) The chambered heart at E10.5 (F) and E14.5 (G), with lineage contributions from the FHF, SHF, cardiac neural crest (CNC) and epicardium (Epi). Ao, aorta; RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle; OT, outflow tract; PT, pulmonary trunk.

Fig. 3.

Formation of the coronary vasculature. At E12.5 (left) the coronary vessels begin to form around the sinus venosus (SV) progressing apically (arrows) across the right ventricle (RV) and left ventricle (LV). The schematic on the right illustrates the adult coronary vascular tree.

Fig. 4.

Stem cell populations in the adult heart. Multiple different stem cell populations have been described in the adult heart, including (from left to right) ISL1⁺ cells, epicardium-derived cells, KIT⁺ cells, SCA1⁺ cells and PDGFRα⁺ cells as well as cardiospheres and side population cells (not shown). (A) Rare ISL1⁺ cells are present in the adult heart only in the conduction system including the sinoatrial node (arrows). Cells were marked by β-galactosidase staining (blue) from an Isl1-nuclear lacZ knock-in allele. Reproduced with permission (Weinberger et al., 2012). (B) The epicardium (shown in red, along with the coronary vessels within the myocardium) gives rise to perivascular cells and stromal fibroblasts in development, and in the adult this potential is retained, which is activated after injury. Other cardiac cells are stained with DAPI (blue). Scale bar: 500 μm. Reproduced with permission from Riley and Smart (2009). (C) KIT⁺ cells are a minor population in the adult mouse heart shown by expression of a Kit-Cre allele (green) and staining for the endogenous KIT protein (red). The inset box shows two mononuclear KIT-expressing cells (arrowheads). Reproduced with permission (van Berlo et al., 2014). (D) Heterogeneous SCA1⁺ cells are present within the interstitium of the adult heart, shown here with SCA1⁺ cells marked by GFP (green), phalloidin (red) showing cardiomyocytes, and DAPI (blue). SCA1⁺ cells include microvascular cells and different stem cell fractions. Reproduced with permission (Uchida et al., 2013). (E) PDGFRα-expressing cells can be detected using a nuclear green fluorescent protein (GFP) expressed from a mouse Pdgfra knock-in allele. GFP⁺ cells are present throughout the cardiomyocyte interstitium and within the adventitial zone of coronary arteries. Red indicates immunofluorescence staining for collagen VI (an adventitial collagen) and blue marks smooth muscle cells positive for α-smooth muscle actin. Original figure reproduced with permission from Vaibhao Janbandhu (Victor Chang Cardiac Research Institute, Australia). Adult heart in figure created using Servier medical art.