Role of Circulating Osteogenic Progenitor Cells in Calcific Aortic Stenosis

Abstract

Objectives The purpose of this study was to determine the role of circulating endothelial progenitor cells with osteoblastic phenotype (EPC-OCN) in human aortic valve calcification (AVC). Background Recent evidence suggests that rather than passive mineralization, AVC is an active atherosclerotic process with an osteoblastic component resembling coronary calcification. We have recently identified circulating EPCs with osteogenic properties carrying both endothelial progenitor (CD34, KDR) and osteoblastic (osteocalcin [OCN]) cell surface markers. Methods Blood samples from controls (n = 22) and patients with mild to moderate calcific aortic stenosis (mi-moAS, n = 17), severe calcific AS (sAS, n = 26), and both sAS and severe coronary artery disease (sCAD) (n = 33) were collected during diagnostic coronary angiography. By using flow cytometry, peripheral blood mononuclear cells were analyzed for CD34, KDR, and OCN. Resected normal and calcified aortic valves were analyzed histologically. Results Patients with mi-moAS and patients with sAS/sCAD had significantly less EPCs (CD34+/KDR+/OCN−) than controls. Patients with sAS showed significantly higher numbers of EPC-OCN (CD34+/KDR+/OCN+) than controls. In addition, the percentage of EPC costaining for OCN was higher in all disease groups compared with controls. A subgroup analysis of younger patients with bicuspid sAS showed a similar pattern of significantly lower EPCs but a high percentage of coexpression of OCN. Immunofluorescence showed colocalization of nuclear factor kappa-B and OCN in diseased and normal valves. CD34+/OCN+ cells were abundant in the endothelial and deeper cell layers of calcific aortic valve tissue but not in normal aortic valve tissue. Conclusions Circulating EPC-OCN may play a significant role in the pathogenesis and as markers of prognostication of calcific AS.

Endothelial damage and vascular calcification in patients with chronic kidney disease

“…Moreover, EPCs that express OCN have been found in greater numbers in calcified aortic valve tissue (17). In our study, we also obtained OCN ϩ EPCs when we cultured EPCs from healthy donors with MPs derived from CKD patients, a finding that reinforces the potentially dominant role played by MPs in the development of VC.…”

In Situ Vascular Tissue Remodeling Using Biodegradable Tubular Scaffolds With Incorporated Growth Factors and Chemoattractant Molecules

“…Calcification in these tissues follows the accumulation of macrophages, and its final stage is accompanied by the induction during inflammation [14]. Importantly, a new concept suggesting that progenitor cells circulating in the blood under certain conditions can exhibit their osteogenic potential and promote intimal [21] and valvular calcification [22] has recently emerged. It was shown that with increasing progression of aortic valve stenosis, the number of circulating osteocalcin-positive endothelial progenitor cells (CD34 + / OCN +) increased with their subsequent accumulation in the calcified aortic valve tissue [22].…”

“…Importantly, a new concept suggesting that progenitor cells circulating in the blood under certain conditions can exhibit their osteogenic potential and promote intimal [21] and valvular calcification [22] has recently emerged. It was shown that with increasing progression of aortic valve stenosis, the number of circulating osteocalcin-positive endothelial progenitor cells (CD34 + / OCN +) increased with their subsequent accumulation in the calcified aortic valve tissue [22]. Thus, this cascade results in the deposition of calcium, primarily in the zones with critical stress [14].…”

CD34-negative mesenchymal stem-like cells may act as the cellular origin of human aortic valve calcification

“…Osteogenic endothelial progenitor (EP) cells, such as vascular endothelial growth factor receptor-2/CD34-positive cells, contribute to aortic valve calcification in atherosclerosis patients [9][10][11]. Furthermore, two recent studies reported that aortic valve calcification is associated with ectopic ossification induced by various bone marrow-derived circulating osteogenic progenitor (COP) cells, such as type I collagen/CD45-positive and/or osteocalcin/CD45-positive cells [12,13].…”