Date of Award

2017

Document Type

Thesis - MUSC Only

Degree Name

Master of Biomedical Science

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Andy Wessels

Second Advisor

Jeremy L. Barth

Third Advisor

Kimberly E. McHugh

Fourth Advisor

Russell A. Norris

Fifth Advisor

Sinai Zyblewski

Abstract

Congenital heart defects (CHDs) are the most common type of birth defect affecting 8 out of every 1,000 newborns.30,31 Persistent Truncus Arteriosus (PTA) comprises 1% of all CHDs and involves the malformation of the outflow tract (OFT) of the heart. The OFT connects the embryonic ventricles with the aortic sac. In normal heart development the aorta and the pulmonary trunk develop via septation of the OFT through the formation of the aorticopulmonary septum by the cardiac neural crest (CNC) cells. Thus, the CNC cells are known to play an important role in OFT septation. Another key cell type involved in OFT development is second heart field (SHF) cells. SHF cells are a population of cardiac progenitor cells in the pharyngeal mesoderm that give rise to OFT myocardium, smooth muscle, and endothelial cells. Although it is known that signaling between CNC cells and SHF cells is required for OFT development, the molecular mechanisms involved have yet to be fully delineated. The overall goal of this study was to describe the development of the OFT in a model for PTA with emphasis on the contribution of the SHF. The Mef2c-AHF-cre;Alk3fl/fl and Mef2c-AHF-cre;Smofl/fl mouse models described in earlier studies in the Dr. Andy Wessels' lab were used in this study, since both models produced conditional knockouts with PTA at a rate of 100% and 87%, respectively. Embryos were collected at embryonic days 10.5, 11.5, and 12.5. It is during these stages in embryonic development that the CNC cells migrate into the outflow tract to form the aorticopulmonary septum. After analyzing Mef2c-AHF-cre;Alk3fl/fl specimens using hematoxylin eosin staining and immunohistochemistry we found abnormal OFT septation and remodeling, a 100% penetrance of PTA in ED12., a decreased number of SHF cells, a decreased proliferation of SHF cells, and a thinning of the OFT myocardium in conditional knockout embryos. This study established that BMP signaling in the SHF is important to the proper development of the OFT myocardium. This study also established that the Mef2c-AHF-cre;Smofl/fl mouse model serves as a reliable model for studying the pathogenesis of PTA, while the Mef2c-AHF-cre;Alk3fl/fl mouse model does not.

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