UC San Diego

Temporally distinct cell lineages give rise to myocardial components of the heart during the complex morphogenesis of cardiac development. Previous work has described the first and second heart fields that give rise to cardiomyocytes, as well as the neural crest and proepicardium that give rise to most non-cardiomyocyte populations within the heart. T-box18 (Tbx18) is a transcription factor that is expressed very early in the developing proepicardium. The role of Tbx18 and the proepicardium during mammalian heart development and maintenance has not been shown. This thesis shows that Tbx18 expressing proepicardial cells give rise to cardiac myocytes, in addition to vascular support cells, resident fibroblasts, and the single-cell covering of the adult heart. The pluripotency of Tbx18 proepicardial cells provides a theoretical framework for applying these progenitors to effect cardiac repair and regeneration. Previous work has shown that the epicardium is a critical source of multiple cell types associated with complex cardiac morphogenesis and physiology. Ablation or disruption of the epicardium during development can lead to abnormalities in the compaction of the myocardial layer, looping, septation, coronary vascular formation, conduction system formation, and cushion tissue formation. Here, we show that ablation of Tbx18 in cardiac progenitors leads to abnormal morphological and physiological development of the heart. Understanding gene regulation in cardiac progenitor cells and the adult epicardium may be a critical step toward clinically relevant strategies in regenerative medicine utilizing the heart's own developmental pathways. Processes associated with heart disease, such as fibrosis and hypertrophy, usually precede cardiac failure. Cardiac failure due to heart disease is associated with myocyte loss secondary to ischemia. Regenerative therapies for the heart will need to address the loss or dysfunction of multiple cell types. Because epicardial cells contribute multiple cardiac cell types during development, they could be more useful in repairing the heart than any single kind of cell. We show that Tbx18 expressing embryonic epicardial cells mediated wound healing in a murine cardiac explant culture. Furthermore, Tbx18 expression was activated in adult epicardium in response to injury. It is likely that some of the pathways involved in fetal healing are initiated in the adult, but prevented by overriding events such as fibrosis, wall thinning, and hypertrophy. Regenerative therapies for the heart may lie in the ability to harness the epicardium as a novel source of cardiac progenitor cells