Abstract 11774: Bi-Directional Vascular Calcifying Progenitor Cells Differentiate Into Decalcifying Cells Via Ppar-γ Activation
Vascular calcification is an advanced feature of atherosclerosis. But, no effective therapy is available. We investigated the characteristics of vascular calcifying progenitor cells and their calcifying/ decalcifying potentials. Cells from aortas of C57 mice were sorted into 4 groups using Sca-1 and PDGFRα. Sca-1+ cells were clonally expanded from single cell. Sca-1+ cells were found to have greater osteoblastic differentiation potentials than Sca-1- cells. Interestingly, under RANKL and M-CSF treated condition, Sca-1+/PDGFRα-cells differentiated into osteoclasts 3 fold more than Sca-1+/PDGFRα+ cells (P<0.01). To trace the origins of cells, we conducted bone marrow (BM) transplantation using GFP + cells. BM-derived, vessel-resident Sca-1+/PDGFRα+ cells differentiated into the osteoblastic lineage uni-directionally, whereas Sca-1+/PDGFRα- cells were capable of differentiating into osteoblastic and osteoclastic lineages bi-directionally ex vivo. Furthermore, PPARγ activation, even under osteoblastic differentiation-inducing conditions, enhanced the osteoclastic differentiation of Sca-1+/PDGFRα- cells. Next, we performed two kinds of in vivoexperiments; ectopic and atherosclerotic calcification. CT scoring of ectopic calcified nodules showed that the injection of Sca-1+/PDGFRα- cells increased bone volume and calcium score compared to PBS injection. Moreover, Sca-1+/PDGFRα- cells with PPARγ agonist decreased bone formation 2 fold, compared to Sca-1+/PDGFRα- cells without PPARγ agonist (P<0.01). The injection of Sca-1+/PDGFRα- cells into Apoe-/- mice increased the calcified atherosclerotic plaques. However, Sca-1+/PDGFRα- cells with PPARγ activations markedly deceased atherosclerotic plaque and calcium accumulations (2.5 fold decrease compared to PBS injection, P<0.01). Immunofluorescent staining showed that Sca-1+/PDGFRα- cells mainly expressed osteocalcin, but, when PPARγ activation, Sca-1+/PDGFRα- cells expressed RANK, indicating the in vivo bi-directional fate. These findings suggest that a subtype of BM-derived, vessel-residing progenitor cells offer a therapeutic target for the treatment of vascular calcification, and that PPARγ activation may provide a means of reversing calcification.
- © 2011 by American Heart Association, Inc.