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Title page for ETD etd-12052008-144450

Type of Document Dissertation
Author Misfeldt, Andrew Michael
URN etd-12052008-144450
Title Endocardial cells are a distinct endothelial lineage derived from multipotent cardiovascular progenitors
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Christopher V.E. Wright Committee Chair
Antonis Hatzopoulos Committee Member
Guoqiang Gu Committee Member
H. Scott Baldwin Committee Member
Tsutomu Kume Committee Member
  • BAC recombineering
  • Heart development
  • Endocardium
  • Mouse transgenesis
  • Embryonic stem cells
  • Heart -- Differentiation
  • Heart cells
Date of Defense 2008-08-27
Availability unrestricted
Identification of multipotent cardiac progenitors has provided fresh insight into the mechanisms of myocardial lineage specification, yet has done little to clarify the origin of the endocardium. Despite its essential role in heart development, the lineage classification of endocardium has remained undefined due to a lack of specific markers of this early vascular subpopulation. To distinguish endocardium from other vasculature, we generated an NFATc1-nuc-LacZ BAC transgenic mouse line that faithfully recapitulated endogenous NFATc1 expression in the heart and other cell populations during development. Utilizing this novel specific marker, the endocardium can be distinguished from other endothelial subpopulations, and tracked as it emerges from the cardiac mesoderm and participates in early cardiac morphogenesis.

To further characterize endocardiogenesis, embryonic stem cells (ESCs) derived from NFATc1-nuc-LacZ blastocysts were utilized to demonstrate that endocardial differentiation occurs in a pattern consistent with its mesodermal origin and its close association with myocardium. Endocardium is specified as a cardiac cell lineage, independent from other vascular populations, responding to BMP and Wnt signals that enhance cardiomyocyte differentiation. Furthermore, a population of Flk1+ cardiovascular progenitors, distinct from hemangioblast precursors, represents a mesodermal precursor of the endocardial endothelium, as well as other cardiovascular lineages. Taken together, this work emphasizes the endocardium as a unique cardiac lineage and provides further evidence that endocardium and myocardium are derived from a common precursor. Furthermore, we have established a method to identify the endocardium at the onset of differentiation and throughout subsequent stages of development, providing the framework for future work to delineate mechanisms important in the ontogeny of this unique population.

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