The Role of Neural Crest Progenitors in the Development of Ventricular Outflow Tract Defects
Abstract
Topic Area: Congenital Heart Disease Congenital heart disease (CHD) is the leading inborn cause of death in infants. Due to early detection and surgeries to correct the anatomical defects, today many patients with CHD have life expectancy close to their healthy peers. However, surviving patients with congenital defects frequently develop complications requiring hospitalization. This has placed a significant burden on the healthcare system. A better understanding of how the normal heart develops will provide important information about CHDs. This, in turn, will help explore new therapies to treat this complex disease. The ventricles are the pumping chambers of the heart, and they eject blood through a conduit, known as the outflow tract (OFT), to the vascular tree. Defects in OFT formation account for nearly 30% of all CHDs. During the early phases of heart development, different types of heart progenitors contribute to OFT formation. A specialized type of progenitors, known as neural crest (NC) cells, have been shown to play an important role in this process. These cells migrate to the heart, where they merge with other progenitors to populate the OFT. However, it is not known what mature cell types are generated by these NCs and what their precise roles are in shaping the OFT. Recent studies have suggested that NC progenitors can differentiate to cardiomyocytes, which are mainly responsible for the contractile properties of the heart. This surprising finding also suggests that cardiomyocytes generated from NC progenitors may contribute to the walls around the OFT and influence OFT development. Defects in NCs leads to a variety of different congenital heart diseases, all of which involve the OFT. Therefore, it is important to determine the role of NC-derived cardiomyocytes in heart development and, in particular, OFT formation. In this proposal, the team attempts to explore the fate of NC cells during heart development and determine how these cells may contribute to OFT defect and CHD development. This is a multidisciplinary proposal that consists of investigators with expertise in heart development, stem cell biology, and cardiology. The team hypothesizes that a distinct population of NCs differentiates to cardiomyocytes and influences OFT development. In this study, both zebrafish and mice will be used as animal models. Zebrafish is a vertebrate animal that allows for the large-scale unbiased screen. In addition, because zebrafish embryos are transparent, researchers can follow a specific cell population in real time to study how they move, multiply, and differentiate during development. This proposal will leverage these unique characteristics of zebrafish to screen a library of compounds. This will identify important genes controlling the migration of NC progenitors to the heart and genes that determine the differentiation of NC progenitors to cardiomyocytes. Furthermore, advanced genetically engineered mouse models will be used to label single NCs during development and track their fate, location, and contribution to the growing OFT. Gene expression at an individual cell level will be evaluated to explore how NCs make their fate decisions as they differentiate and migrate throughout the heart. At the completion of the proposed project, new insights into how neural crest cells contribute to heart development will be gained. As the processes for heart development are largely conserved among vertebrates, insights gained from this project will inform how neural crest cell influence OFT formation in humans and will help design new therapies for CHD patients with OFT defects.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110150
Entities
People
- Jau-Nian Chen
Organizations
- United States Army
- University of California, Los Angeles