Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Genetics and Genomics

Language

English (en)

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

David Ornitz

Abstract

In this thesis I examined the function of Fibroblast Growth Factor: FGF) signaling in epicardial cells. Epicardial cells serve as the outer layer of the heart and as a signaling center for the growing myocardium. In addition, during development, epicardial cells differentiate into vascular smooth muscle cells: vsmc) and interstitial fibroblasts. Epicardial cells undergo an epicardial to mesenchymal transition: EMT) to give rise to these various cell types, which are termed epicardial derived cells: EPDCs). Epicardial-derived vsmc are an essential component of the arterial network in the myocardium, and the interstitial fibroblasts become part of the fibrous skeleton of the myocardium. To populate the myocardium, EPDCs must migrate through the subepicardial space and into the compact myocardium. Very little is known about how this migration is initiated, maintained and guided. Although, FGF7 and FGF10 are expressed in the myocardium their function was not known. Biochemically, these FGFs activate the b splice variants of FGFR1 and FGFR2. Here, I show that FGF10 siganls to the epicardium in vivo to induce migration of EPDCs. Furthermore, I found that FGF10 promotes migration of EPDCs that are fated to become interstitial fibroblasts. Embryonic cardiac fibroblasts are important during late heart gestation because they induce proliferation of cardiac myocytes. In hearts in which the FGF10/FGFR2b signaling pathway is disrupted, cardiac fibroblasts fail to migrate into the myocardium. I posit that fewer interstitial cardiac fibroblasts results in decreased cardiac myocyte proliferation and a smaller heart. Other growth factors like PDGFβ had been identified to activate migration of epicardial-derived vsmc but not cardiac fibroblast. Thus it appears that specific extracellular signaling pathways are required to control the migration of EPDC-lineages into the myocardium. These findings are an important contribution to the understanding of epicardial development. Epicardial and EPDC are not only important for heart development, but are thought to be essential for heart repair and regeneration due to the potential of these cells to differentiate in various cell types.

DOI

https://doi.org/10.7936/K76971KW

Comments

Permanent URL: http://dx.doi.org/10.7936/K76971KW

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