We currently have two major areas of research focus. One concerns the molecular mechanisms that control formation and differentiation of coronary vessels during heart development. The other is on vascular stem and progenitor cells that reside in the adventitial layer of artery wall.
Developmental fate mapping studies show that progenitor cells in the proepicardium (PE) give rise to coronary vessels. Formation of coronary vessels occurs by an epithelial to mesenchymal transition (EMT) of epicardial cells followed by vasculogenesis in the subepicardial space, assembly and remodeling of a primitive coronary plexus, and investment by pericytes and coronary smooth muscle cells (CoSMCs).
While these basic steps in coronary development are well established, the molecular mechanisms that control specification of PE cells to vascular progenitors, and the signaling pathways that couple epicardial cell EMT to transcriptional activation of CoSMC differentiation marker genes are still largely unknown. We are using transgenic and gene knockout approaches to examine the role of hedgehog and notch signaling pathways in coronary vessel development. Specifically, we are studying the molecular mechanisms by which epicardial cell-cell adhesion maintains epicardial-specific gene expression and represses CoSMC-specific gene transcription.
The second main project in the laboratory is on the development and characterization of a newly discovered vascular stem and progenitor cell niche within the adventitial layer of artery wall. Our initial studies identified a novel sonic hedgehog (Shh) signaling domain restricted solely to the adventitia. Within this Shh signaling domain we found a population of stem cell antigen-1-positive (Sca1+) progenitor cells capable of differentiating to SMCs, pericytes, adipocytes, and osteogenic cells.
These current studies aim to understand the molecular genetic pathways that maintain these cells as self-renewing and undifferentiated progenitors within the arterial adventitia. We are also evaluating the role played by adventitial Sca1+ progenitor cells in angiogenesis of the vasa vasorum and in repair, remodeling and disease of the artery wall.
For students interested in either of these areas of focus in the laboratory, please contact Mark Majesky to discuss current rotation projects.