Abstract 16645: Endothelial-Like Progenitor Cells Generate Ventricular Cardiomyocytes During Cardiac Homeostasis and Myofibroblasts After Injury
During development, cardiovascular progenitor cells expressing the endothelial-specific gene VEGFR-2 differentiate into all major cell types of the heart. We hypothesized that an endothelial-like progenitor population exists in the adult heart, contributing to cardiac homeostasis and tissue repair after injury. To test this model, we traced endothelial cell fates using three independent transgenic mouse lines with constitutive Cre recombinase expression in endothelial cells (Tie1.Cre, VE-Cadherin.Cre), or inducible endothelial-specific Cre expression to label adult endothelial cells (End-SCL.CreERT) crossed to ROSA.LacZ or ROSA.EGFP mice. In all lineage-tracing models, we observed labeling of both endothelial cells (ECs) and ventricular cardiomyocytes (CMs) within the healthy adult heart. Whereas EC labeling was homogeneously distributed throughout the entire myocardium, CMs of EC origin were localized within specific patches in the subepicardial area near coronary arteries. Use of the ROSA.Brainbow-2.1 reporter line demonstrated that each CM patch was of a distinct clonal origin.
Employing the inducible End-SCL.CreERT line, we pulse-labeled ECs and followed their fate both short and long-term during homeostasis. We found that EC-derived CMs had a transient lifespan, reaching peak numbers three weeks after EC labeling, but declining thereafter. From these pulse-labeling studies, we estimated a global annual turnover rate of 0.4% for EC-derived CMs in the adult mouse heart. Interestingly, the regenerative rates of EC-like progenitors declined significantly after LAD ligation in a myocardial infarction (MI) model. Instead, these cells contributed almost exclusively to scar tissue formation through generation of infarct myofibroblasts.
In summary, our findings suggest that an EC-like progenitor population exists in the adult heart with cardiomyogenic regenerative capacity that replenishes high turnover CMs within localized ventricular sites. In contrast, these progenitor cells acquire a pro-fibrotic phenotype after MI. Understanding the biology of this novel adult progenitor population may lead to new methods of enhancing the regenerative capacity of the heart after acute ischemic injury or during heart failure.
- © 2013 by American Heart Association, Inc.