Discovered in 1994, fibrocytes are bone marrow-derived mesenchymal progenitors that co-express hematopoietic stem cell genes, selleck chemicals markers of the monocyte lineage, and fibroblast products. Fibrocytes constitute another source of circulating cells able to differentiate in fibroblasts, myofibroblasts and adipocytes[45]. In valve and arteries, myofibroblasts contribute to cardiovascular ossification; Vattikuti observed that adventitial activated myofibroblasts cells are diverted to the osteoblasts lineage: the hypothesis is that myofibroblasts, responding to vascular smooth

muscle cell osteopontin production contributes to calcification in diabetes. Moreover pericytic myofibroblasts expressed BMP-2, a powerful bone morphogen[46]. RESIDENT STEM CELLS Mesenchymal stem cells Bone marrow-derived MSC which reside in the vessel wall can differentiate in several cell types, including osteoblasts, chondrocytes and endothelial cells[47-51]. Previous results from our group showed that it is possible to isolate and culture spindle-shaped resident cells with the characteristics of MSC directly from the vessel wall of thoracic aortas harvested from multiorgan and tissue donors. These vessel-wall MSC (vw-MSC)

are CD45- and show low expression for CD34, but most co-express CD44, CD90 and CD105, like the bone marrow-derived MSC[52]. Moreover, at reverse transcription polymerase chain reaction these cells express transcripts of embryonic stem cell (OCT4, IL6 and BCRP-1) and hematopoietic stem cell (c-Kit, BMI-1)[52]. Years after we confirmed that vw-MSC expressed the stemness markers Stro-1, Notch-1 and OCT4, and that they were able to differentiate into adipogenic, chondrogenic and leiomyogenic lineages, when cultured in induction media[53]. Recently, Klein et al[54] described a CD44+ population of “vascular wall-resident multipotent

stem cells”, expressing also CD90 and CD73, and negative for CD34 and CD45. Moreover, vw-MSC were also isolated and cultured from arterial specimens frozen up to 5 years, and showed positivity for Brefeldin_A HLA-G, Stro-1, Oct-4 and Notch-1, in addition to the above mentioned[55]. Recently it was hypothesized that MSC might play a role in the pathogenesis of atherosclerosis, and it was demonstrated that, under particular conditions, MSC in culture acquire an osteoblastic phenotype via the activation of the Wnt pathway[56]. In hyperlipidemic rats treated with angioplasty to have a vascular damage, MSC started the vessel wall remodelling and triggered calcification, mediated by paracrine BMP-2[57], which is considered one of the main mediators in the differentiation of MSC (and others) along the osteoblastic lineage[58,59]. Interestingly, MSC cultured in a uremic serum for one month (mimicking partly the renal failure stimuli) hyperexpressed alkaline phosphatase, osteopontin, Runx2 and showed an up-regulation of BMP-2[60].