The concept of atherosclerotic plaque formation as the cause of obstructive vascular disease was proposed more than 100 years ago. Our understanding of atherosclerosis is being continually modified to include vessel wall responses from resident endothelial cells, smooth muscle cells, fibroblasts and circulating blood cell responses from macrophages, lymphocytes and platelets.
However, a number of experimental/human studies have called into question the origin of traditionally accepted cellular constituents of atherosclerotic plaque, suggesting that circulating, bone marrow or extravascular sources of precursor cells may be crucially important in reconstituting/remodelling endothelial and vascular smooth muscle elements within the diseased vessel wall.
Recently our group isolated and characterized a putative common progenitor cell which possesses multiple angioblastic and myeloid markers. We have shown that committed endothelial and smooth progenitor cells (EPC and SPC) can be differentiated from vascular progenitor cells (VPC) in vitro and that these progenitors can be isolated from mice, rats, pigs and humans.
VPC exhibit multiple stem-like features, including clonogenic expansion capacity, unlimited self-renewal, expression of high levels of telomerase and vascular reconstitution capacity. Importantly, adult VPC plasticity appears driven not only by traditional vascular growth or differentiation factors but also by cell-cell contact activation. Study of VPC plasticity may therefore allow fundamental new insights into progenitor composition and remodelling of atherosclerotic plaque.
Currently nothing is known about the mobilization, lineage differentiation, homing or integration of these cells in experimental models of atherosclerosis. Therefore the overall objective of this proposal will be to determine the biology of VPC in experimental atherosclerosis, and the therapeutic potential of VPC when used to treat obstructive vascular disease and its complications.
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