Date of Award

Fall 11-14-2024

Embargo Period

11-18-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Andy Wessels

Second Advisor

Russell Norris

Third Advisor

Robin Muise-Helmericks

Fourth Advisor

Paula Ramos

Fifth Advisor

Ge Tao

Abstract

Congenital heart defects (CHDs) are the most common birth defects in humans, affecting as many as 1% of live births, thereby representing a major public health burden. These defects arise when signaling pathways and mechanical forces guiding heart development are disrupted, either by genetic mutations, aneuploidies, environmental influences, or any combination of these factors. The vast majority of CHDs have undetermined etiologies. Understanding the molecular and cellular mechanisms of normal heart development is critical for unraveling the origins of CHDs and for developing more effective diagnostics and interventional treatments for those affected by cardiovascular diseases of developmental origin.

The epicardium is a single-cell layer of progenitor cells lining the outside of the heart. Epicardial-derived cells (EPDCs) play important roles in the proper development and homeostasis of the atrioventricular (AV) valves, myocardium, and coronary vasculature. This thesis describes a novel role for the transcription factor SOX9 in regulating the contribution of EPDCs to the developing heart. We utilize transgenic lineage-tracing mouse models, high-resolution immunofluorescence analyses, bulk, and single-cell RNA-sequencing (scRNA- seq) to understand the morphological, cellular, and molecular changes associated with epicardial-specific deletion of Sox9. These studies demonstrate that loss of Sox9 results in a marked impairment in the invasion of EPDCs into both the AV valves and the ventricular myocardium. This impaired invasion results in pathogenic changes to the mitral valve reminiscent of myxomatous mitral valve disease (MVD) in humans. Reduced EPDC invasion due to loss of Sox9 also delays the development of the myocardium and the coronary vascular plexus. Sequencing experiments identified Cd109 as a novel gene associated with myxomatous valve pathogenesis in this model. Overall, these studies support an important role for Sox9 in the regulation of epicardial invasion critical for proper heart development and AV valve homeostasis. We also identify Cd109, a gene never previously described in the context of heart development or disease, as a novel player in various cardiovascular developmental events. These insights contribute to a better understanding of etiologies of cardiovascular diseases with developmental origins.

Rights

Copyright is held by the author. All rights reserved.

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