Abstract 12143: The Identification of Bone Marrow-derived Artery-resident Mesodermal Progenitor Cells and Dynamics in Atherosclerosis

Abstract

Background: Cellular components and dynamics play a pivotal role in vascular diseases. A recent study identified bone marrow (BM)-derived calcifying progenitor cells. However, the nature of progenitor cells remains elusive. We here investigated the developmental hierarchy of progenitor cells and their dynamics in atherosclerosis. Methods and Results: We harvested cells from BM and artery of C57 mice. In BM, Lin-/CD29+/Sca-1+/PDGFRα- cells showed hematopoietic potential and differentiated into osteoclast (OC)-like cells.They also possessed mesenchymal stem cell property including osteoblastic (OB) differentiation. In contrast, Lin-/CD29+/Sca-1+/PDGFRα+ cells showed only OB potential. In vivo reconstitution assay demonstrated that Sca-1+/PDGFRα- cell was an ancestor of Sca-1+/PDGFRα+ cell, suggesting a mesodermal progenitor cell. Interestingly, BM-derived artery-resident, clonal Sca-1+/PDGFRα- cells maintained bi-potency (OB/OC) but lost hematopoietic nature. When we stimulated or knocked down PDGFRα, there was no alteration in OB or OC differentiation of Sca-1+/PDGFRα- cells and no effect on OB differentiation of Sca-1+/PDGFRα+ cells, indicating PDGFRα as a surface marker but not a functional player. In Apoe-KO mice compared with control, Sca-1+/PDGFRα- cells were less mobilized from BM to peripheral circulation and less infiltrated into atherosclerotic plaque, whereas Sca-1+/PDGFRα+cells were not significantly affected. Multiplex cytokine assay of serum and artery revealed that IL-1β was modestly increased and IL-5 was markedly decreased in atherosclerotic mice. IL-1β decreased the migration of Sca-1+/PDGFRα- cells by 5 folds compared with TNFα, and IL-5 increased the migration as much as TNFα. But the migration of Sca-1+/PDGFRα+ cells was not altered. Conclusion: We demonstrate that Sca-1+/PDGFRα- cell is a mesodermal progenitor cell that possesses both hematopoietic and mesenchymal potentials. The mobilization and infiltration of mesodermal progenitor cells into artery were regulated by atherosclerosis-related Inflammatory and anti-inflammatory humoral factors. These data may have implications for the pathophysiology of atherosclerosis and provide a novel therapeutic target for vascular diseases.