Publication Date

2012-05-01

Availability

Open access

Embargo Period

2012-05-01

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cell Biology and Anatomy (Medicine)

Date of Defense

2012-04-03

First Committee Member

Joy Lincoln

Second Committee Member

Xiangxi Mike Xu

Third Committee Member

Nanette H. Bishopric

Fourth Committee Member

Teresa A. Zimmers

Abstract

Congenital cardiovascular defects (CHD) are the most common causes of infant death from birth defects (Lloyd-Jones, Adams et al. 2010). In the United States, over 25,000 cases with myocardial defects such as hypoplastic left heart syndrome were recorded in 2001. Beyond this astonishing number, an estimated 3 million more people have bicuspid aortic valve (BAV) (Rosamond, Flegal et al. 2008). Despite the clinical significance, there is a lack of effective therapies for treating CHDs, with surgical intervention as the most common treatment. Thus understanding the normal development of these affected cardiac compartments may provide novel insights and therapeutic targets of CHDs. In the primitive heart, the endocardium and epicardium specifically contribute to heart valves and myocardium maturation respectively, by undergoing epithelium/endothelium to mesenchyme transformation (EMT) to generate progenitors cells that give rise to these mature structures. Heart valves are dynamic and delicate structures that maintain unidirectional blood flow throughout life. Insufficient valve function, commonly due to congenital malformations leads to disruptions in hemodynamics and eventual heart failure. During development, the valves are derived from primordial structures called endocardial cushions, formed by EMT in the atrioventricular endocardium. Endocardial cushions elongate into valve primordium, which will later remodel into valve leaflets. Mature valve leaflets are composed of a heterogeneous population of interstitial cells and stratified extracellular matrix, surrounded by a layer of endothelial cells. This cell-matrix composition provides the valve with all the necessary biomechanical properties required to efficiently function while withstanding constant cyclic shear stress. In addition to development, VECs are also important for maintaining life-long valve integrity and function through the adaptation to the constantly changing hemodynamic environment. Besides VECs, which locate at the lumen-side of the heart chamber, the epicardium, covering the outer surface of myocardium, also gives rise to a group of cardiac progenitors called epicardial-derived cells (EPDCs) through EMT. Following EMT, EPDCs invade the myocardium and differentiate into vital components of the functional myocardium including smooth muscles cells of the coronary vessels, cardiac fibroblasts and a small portion of cardiomyocytes. In the current studies, we showed that Snai1, a zinc-finger transcription factor, is expressed in endocardial cushion cells, VECs in valve primordium, as well as epicardium and EPDCs during normal embryogenesis. Although Snai1 has been widely studied in other EMT model such as cancer metastasis and gastrulation, its direct role during heart development has not been clarified. Our data indicate that Snai1 function is required for endocardial cushion formation, valve remodeling and epicardial development; conditional loss-of-function of Snai1 in endocardial cushion cells and VECs of the remodeling valves leads to abnormal valvular structure. We also identified matrix metalloproteinase 15 (mmp15) as a novel target gene of Snai1, while knock-down of Snai1 in epicardial cells results in a thinner ventricular walls.. Together these studies characterize the specific function of Snai1 during cardiogenesis and improve our understanding of heart valve and epicardium development, which may favor the development of novel treatments for valvular and myocardial disease in the future.

Keywords

Snai1; heart valve; epicardium; development

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