Abstract
Cardiac neural crest cells contribute to important portions of the cardiovascular system including the aorticopulmonary septum and cardiac ganglion. Using replication incompetent avian retroviruses for precise high-resolution lineage analysis, we uncover a previously undescribed neural crest contribution to cardiomyocytes of the ventricles in Gallus gallus, supported by Wnt1-Cre lineage analysis in Mus musculus. To test the intriguing possibility that neural crest cells contribute to heart repair, we examined Danio rerio adult heart regeneration in the neural crest transgenic line, Tg(-4.9sox10:eGFP). Whereas the adult heart has few sox10+ cells in the apex, sox10 and other neural crest regulatory network genes are upregulated in the regenerating myocardium after resection. The results suggest that neural crest cells contribute to many cardiovascular structures including cardiomyocytes across vertebrates and to the regenerating heart of teleost fish. Thus, understanding molecular mechanisms that control the normal development of the neural crest into cardiomyocytes and reactivation of the neural crest program upon regeneration may open potential therapeutic approaches to repair heart damage in amniotes.
Highlights
The neural crest is an important stem cell population characterized by its multipotency, migratory behavior, and broad ability to differentiate into derivatives as diverse as elements of the cardiovascular system, craniofacial skeleton, and peripheral nervous system
Based on our observation on the lineage relationship between cardiac neural crest cells and cardiomyocytes during development, we propose that neural crest-derived cells may represent a key population that proliferates and differentiates into new cardiomyocytes after injury
Consistent with previous lineage tracing experiments in zebrafish (Cavanaugh et al, 2015), where a proportion of cardiac crest derived-cells were located in the trabeculated myocardium in adult fish, we show that after injury, there is activation of numerous neural crest gene regulatory transcription factors and other neural crest genes during regeneration (Figure 4)
Summary
The neural crest is an important stem cell population characterized by its multipotency, migratory behavior, and broad ability to differentiate into derivatives as diverse as elements of the cardiovascular system, craniofacial skeleton, and peripheral nervous system. Ablation studies in chick embryos show that removal of the cardiac crest results in a broad range of defects, including persistent truncus arteriosus, abnormal myocardium function, and misalignment of the arch arteries (Kirby et al, 1983; Waldo et al, 1999; Bockman et al, 1987) These defects are highly reminiscent of some of the most common human congenital heart defects. Neural crest cells are a group of these stem cells found in all animals with backbones (i.e. vertebrates) including humans These cells migrate extensively during development to form many different parts of the body. These results provide new insights into the repair and healing of damaged heart muscle in fish They show that similar processes could exist in mammals, including humans, suggesting that activating neural crest cells in the heart could treat damage caused by heart attacks and related conditions. These results demonstrate an evolutionarily conserved contribution of neural crest cells to cardiomyocytes across vertebrates and a previously unappreciated role during heart regeneration
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