Pericytes are progenitors for coronary artery smooth muscle [electronic resource]

The vasculature is a network of endothelial-lined tubes covered with mural cells where pericytes associate with small vessels and smooth muscle surrounds larger arteries and veins. Because these cells exist in close proximity, vascular biologists have long wondered whether pericytes and smooth muscle cells interconvert. However, direct evidence has been restricted by limited experimental tools and a lack of knowledge about when and where such differentiation events might occur. Knowing whether pericytes and smooth muscle differentiate into each other, and the mechanisms that stimulate this process, has the potential to impact clinical treatments for cardiovascular disease. Thus, the central aim of this PhD thesis has been to study the lineage relationship between pericytes and smooth muscle and the molecular signals regulating their interactions. I found that, in the heart during embryonic development, pericytes are the progenitors of coronary artery smooth muscle, and that Notch signaling stimulates the pericyte to smooth muscle transition. My studies also provide evidence that smooth muscle cells can revert to a pericyte phenotype during remodeling of the vasculature. Together, these studies answer the long outstanding question of how pericytes and smooth muscle relate and reveal a progenitor cell population and molecular pathway that could be manipulated for coronary artery regeneration. Because understanding coronary artery biology could identify clinical treatments for coronary artery disease, I focused my studies on coronary artery smooth muscle development, which remains a poorly understood process. The first step was to characterize how coronary artery smooth muscle cells form during embryonic development in the intact, three dimensional heart, which had not previously been performed yet at high cellular resolution. My data showed for the first time that, in mice, coronary artery smooth muscle cells differentiate deep within the myocardium around vessels that have just begun to remodel into coronary arteries. Because epicardial cells at the surface of the heart are known to give rise to coronary artery smooth muscle, we took a clonal analysis approach to trace the differentiation events between the epicardium and smooth muscle. Clonal analysis and direct lineage tracing experiments led us to discover that pericytes are the epicardial-derived progenitors for coronary artery smooth muscle cells. Additional clonal analysis revealed that smooth muscle related pericytes are also maintained in the adult heart. As for the molecular regulators, we show evidence that the pericyte to smooth muscle cell transition is stimulated by blood flow induced Jagged and Notch signaling (Chapter 2). This work is the first to show a direct ontogenic relationship between pericytes and smooth muscle and identifies a pathway that could be used to influence smooth muscle differentiation during cardiovascular regeneration. The discovery of a pericyte to smooth muscle differentiation pathway led me to ask whether smooth muscle could be transformed into pericytes. To address this question, I lineage traced mature smooth muscle cells. These experiments resulted in lineage labeled pericytes specifically at the ends of coronary arteries suggesting that mature smooth muscle dedifferentiates during developmental vascular remodeling (Chapter 3). Current methods of coronary artery regeneration fail to produce meaningful repair following cardiovascular injury, which is likely due to our lack of knowledge on progenitor cell populations and the signaling pathways that activate their differentiation. Our discovery that pericytes are epicardial derived coronary artery smooth muscle progenitors could have implications for regenerative medicine as this knowledge could reveal new progenitor cells and targetable pathways for coronary disease.

Advisor: Red-Horse Kristy
Desai Tushar
Palmer Theo advisor. Thesis advisor
Weissman Irving L. advisor. Thesis advisor