Abstract 18445: Embryonic Origins of Vascular Progenitors in the Adult Murine Aorta

Abstract

Background: The vasculature is derived from many different sources during embryonic development, including neural crest, and mesoderm of splanchnic, pharyngeal and somitic origin. Vascular smooth muscle cells (VSMC) of the aorta are similarly derived from several embryonic sources, however the developmental and phenotypic heterogeneity of their progenitors is poorly understood. Methods & Results: Using specialized Cre mice which irreversibly mark cells of specific embryonic origin, we isolated distinct subsets of progenitors from the aorta that are derived from neural crest (Wnt1), somite (Myf5) and another (Brachyury; T) mesoderm source. Intriguingly, a population of lineage-marked cells that express high levels of the reporter tdTomato (tdT-hi) is uniquely expressed in the aorta, and not found in blood, bone marrow or spleen. In Myf5- and T-marked lineages, this tdT-hi population gave rise to clonally-derived spheres that differentiated into VSMC, adipocytes, S100β-positive neural cell and macrophage in vitro. Consistent with the observed progenitor activity of the tdT-hi population, a subset of these cells co-express Sox2 and Sca1, known adult stem/progenitor cell markers. Further evidence of progenitor activity was demonstrated in an in vitro CFU assay where tdT-hi cells gave rise to Mac3+Ly6C+ macrophage and Ly6G+ neutrophils. As experimental cell culture is prone to artifact, and differentiated cell types may not be represented in vivo, we conducted complementary analyses in mice. Leukocytes such as macrophage, B-cells and T-cells from Myf5-Cre mice were found to be lineage-marked cells with lower levels of tdT expression (tdT-lo), suggesting derivation from somitic mesoderm and differentiation from the tdT-hi aortic progenitor. Indeed, somite-derived leukocytes were enriched over 6-fold in the arch of the aorta vs. the blood, bone marrow and spleen of these mice. Summary: These data support the existence of an aorta-resident Myf5 lineage-marked (i.e. somitic mesoderm-derived) progenitor capable of contributing to both VSMC and blood compartments. How these neural crest vs. somite- and other mesoderm-derived aortic-resident progenitors and their progeny participate in vascular pathogenesis is not yet known.