Integrating imaging and computation to characterize neural crest cells in the myocardial development and regeneration Cardiac neural crest cells are a population of highly migratory cells emerging from the neural tube, migrating through the pharyngeal arches and integrating into the developing heart. Recent advances demonstrate that a new sub-population of neural crest cells has the capacity to integrate into the cardiac chamber and differentiate into cardiomyocytes in both zebrafish and mice. Notch signaling regulates cardiomyocyte proliferation and differentiation during ventricular chamber development. Despite the knowledge gained in the past decades, the contribution of neural crest-derived cardiomyocytes to contractile function and the role of these cardiomyocytes in Notch signaling-mediated ventricular remodeling remain elusive. The small heart size in zebrafish embryos and neonatal mice also hinders precise cardiac structural and functional assessment. For these reasons, I seek to integrate our advanced imaging (sub-voxel resolution light-sheet fluorescence microscopy, SV-LSFM) with computation (displacement analysis of myocardial mechanical deformation, DIAMOND) to characterize the structural and functional contributions of the neural crest-derived cardiomyocytes to the myocardial development and regeneration with high spatiotemporal resolution. Under the joint mentorship from Professor Tzung Hsiai (Mechanotransduction, UCLA), Professor Jau-Nian Chen (Developmental biology, UCLA) and Professor Debiao Li (MR imaging, Cedars-Sinai Medical Center), I will continue to collaborate with Professor Atsushi Nakano (Developmental biology, UCLA) and Dr. Adam Langenbacher (Developmental biology, UCLA), and consult with Professor Joseph Wu (Cardiac stem cells, Stanford), Professor Sandra Rugonyi (Oregon Health & Science University), Professor Linda Demer (Vascular biology, UCLA) to test our hypothesis. We hypothesize that neural crest cells contribute to the ventricular myocardium and neural crest-derived cardiomyocytes are essential for the contractile function and ventricular repair. To test this hypothesis, we will have three aims.
In Aim 1, we will elucidate the 4-D migration path of cardiac neural crest cell via SV-LSFM.
In Aim 2, we will demonstrate 4-D structure and function following cardiac neural crest cell contribution to the ventricular myocardium via DIAMOND.
In Aim 3, I will independently quantify the ventricular repair following the ablation of neural crest-derived cardiomyocytes in zebrafish and mouse models with my collaborators. In this context, we believe that the integration of genetic models with advanced imaging and computation will provide new mechanical and developmental insights into the contribution of neural crest cells to contractile function and ventricular repair under the regulation of Notch signaling pathway.
Neural crest defects account for over 10% of all congenital heart disease (CHD), and the migration defect of the cardiac neural crest-derived cells results in septal defects, the most common type of congenital heart anomaly. Despite the existing literature to study the contribution of neural crest cells to the outflow tract (OFT) development, we discovered a new sub-population of cardiac neural crest cells that contribute to the ventricular myocardium at a different developmental stage. For these reasons, we seek to integrate our genetic animal models with advanced imaging and computation to discover, characterize, and elucidate physiologic and pathophysiological migratory paths, leading to heart chamber and septal formation; thus, revealing new developmental insights into the cardiac structure and contractile function.
