Yost Lab Nature Communications Paper
Nov 2, 2018 10:00 AM
The Yost Lab has published a paper in Nature Communications titled, "Loss of Embryonic Neural Crest Derived Cardiomyocytes Causes Adult Onset Hypertrophic Cardiomyopathy in Zebrafish."
Adult-onset cardiomyopathy and heart failure in humans is a major health concern. Approximately 5.7 million adults in the US have heart failure,costing an estimated $30.7 billion each year in health care. Using zebrafish as a discovery model, we have found that disruption of a small group of specialized heart cells (called neural crest derived cardiomyocytes, NC-Cms) during embryonic life predisposes adults to heart failure. In addition, we have found that these cells emit a molecular signal to neighboring cells that is essential for normal heart formation, and inherited mutations in a gene for this cell signal have the same outcome, adult onset heart failure. Our findings provide the first adult zebrafish models of heart failure, one of the most prevalent human diseases, and build a foundation for future studies for therapeutic interventions in juveniles that might prevent adult heart disease.
Neural crest cells invade the embryonic heart and transform into a small number of neural crest derived cardiomyocytes (NC-Cms), but their functions were unknown. We have found that NC-Cms in the zebrafish ventricle are enriched for expression of Notch ligand jag2b, are adjacent to Notch responding cells, and persist as approximately 12% of the cardiomyocyte population throughout life. Embryonic ablation of NC-Cms results in mispatterned trabeculation. We propose that NC-Cms serve as a pre-specified source of topologically patterned Jag2B presentation, which then regulates the spatial patterning of trabeculation.
Strikingly, NC-Cm ablatants have adult-onset hypertrophic cardiomyopathy (HCM) and heart failure. Adult jag2b heterozygotes have mild cardiomyopathy and homozygotes have severe cardiomyopathy. Thus, we have identified two components that are required to prevent adult-onset cardiomyopathy: a novel cardiomyocyte population and a genetic pathway not previously implicated in HCM. Our findings provide the first adult zebrafish models of heart failure, one of the most prevalent human diseases, and will be used to test therapeutic interventions to prevent adult heart failure.
It is remarkable that NC-CM ablatants and jag2b mutants have adult cardiac phenotypes, indicating that they fail to utilize the normal endogenous ability in zebrafish to repair and regenerate. Although they are functional cardiomyocytes, NC-Cms ‘remember’ their embryonic neural crest heritage/history and have distinct transcriptome profiles. We are exploring the hypothesis that NC-Cms serve as resident adult stem cells and/or their embryonic pathways are reactivated for cardiac regeneration. We are now using these profiles to explore the roles of NC-Cms in adult cardiac repair and regeneration, and the evolutionary relationships in hearts of other vertebrates.