Heart2019 · Role of the cardiac neural crest cells in heart development and regeneration

Role of the cardiac neural crest cells in heart development and regeneration

The neural crest is a key stem cell population characterized by its multipotency, migratory behavior, and broad ability to differentiate into many derivatives, such as the craniofacial skeleton, melanocytes, and various parts of the cardiovascular system. The cardiac neural crest (CNC) is one of the most unique neural crest subpopulations that contributes to the proper development of the parts of the heart including the outflow tract, coronary vessels, valves, and cardiomyocytes. Classical and genetic ablation studies in chick and zebrafish embryos showed that removal and dysregulation of CNC development led to a broad range of heart defects and diseases, including persistent truncus arteriosus, cardiomyopathies and heart failure. Heart defects are the most common congenital birth defects in newborns, and defects in septation of the heart and outflow tract are among the most common defects of the general population requiring surgical repair. For example, Jacobsen syndrome is often associated with ventricular septal defects caused by a mutation in Ets-1 gene which is known to be associated with CNC development. The CNC also has a key role in the repair and healing of damaged heart muscle in fish. Recently, it has been shown that zebrafish CNC cells may represent a population of quiescent stem cells that differentiate to cardiomyocytes after myocardium injury by redeploying a neural crest developmental gene regulatory program. Based on our current knowledge, only a limited number of vertebrates are capable of scar-free regeneration of myocardium with newly differentiating cardiomyocytes entirely replacing the injured tissue. Although the data from zebrafish demonstrate that CNC cells proliferate and differentiate into new cardiomyocytes upon injury, not much is known about their role in the heart development and repair in basal vertebrates. Thus, using a multiorganismal approach allowed us to discover fundamental mechanisms driving heart regeneration across vertebrates and better understand the potential of applying this knowledge to heal the human heart after a heart attack and during heart damage. The project had four main objectives as follows: 1. To examine the fate of CNC and identify its developmental potential in lamprey, sturgeon, and salamander. 2. To determine the developmental potential of CNC to differentiate into cardiomyocytes. 3. To define whether CNC cells represent a source of “stem cells” for heart regeneration. 4. To determine whether the mechanism by which CNC cells contribute to heart regeneration is common between basal and jawed vertebrates. In conclusion, this project revealed that CNC and CNC-derived Schwann cell precursors have regenerative potential for heart repair in 'lower' vertebrates and identified potential candidates related to these regenerative mechanisms. Additionally, the developed tools and datasets were used for several related projects. Finally, this grant was an outstanding experience that provided me with multidisciplinary collaborations and helped me prepare for the role of an independent scientist and leading my own research group.

Data: CORDIS, © European Union