Characterisation of progenitor cells in human atherosclerotic vessels☆
Introduction
Atherosclerotic lesions contain a heterogeneous population of cells including endothelial cells (ECs), smooth muscle cells (SMCs), macrophages and lymphocytes [1]. Lesion progression is characterised by a changing cell population from the appearance of an early fatty streak to a more complex cellular, lipid and matrix-rich mass covered by a fibrous cap [2]. Cells migrate and are recruited to the neointimal lesion from the initial phase of lesion formation, including inflammatory cells such as lymphocytes and macrophages from circulating blood [3].
The accumulation of neointimal SMCs is traditionally attributed to SMC migration from the media but recent data has challenged this [4], [5]. Several groups have reported the contribution of circulating progenitor cells to the formation of atherosclerosis in a variety of animal models [6], [7]. In our mouse model of vein graft arteriosclerosis we have shown that 60% of SMC in lesions are derived from the vessel wall and 40% from the host, possibly circulating blood [8]. This implies that a source other than the media is producing neointimal SMCs such as circulating progenitor cells.
In the same model circulating progenitor cells contributed to regeneration of EC in vein graft atherosclerosis [6]. Likewise, in a murine model of allograft arteriosclerosis it was shown that some of the neo-EC were derived from circulating progenitor cells [9]. We have also shown that abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice [10].
From the mouse studies, we can conclude that there are multiple sources for lesional cells including progenitor cells. Human vascular studies have identified reparative roles for circulating progenitor cells [11], [12], [13], [14]. However, little is known about the contribution of progenitor cells to human atherosclerotic lesions.
Thus, the aim of this study was to determine if progenitor cells were present in human atherosclerotic vessels, and if so, to characterise their location and number. We assessed a panel of progenitor cell markers: CD34, VEGF receptor 2 (VEGFR2), stem cell antigen (Sca-1), c-kit and CD133 to identify early progenitor cells, including those of endothelial cell and SMC lineage. We have shown that progenitor cells are present both in neointimal lesions and the adjacent adventitia of human atherosclerotic vessels. Identifying progenitor cells in atherosclerotic lesions further elucidates the potential for these cells to be directly involved in lesion progression.
Section snippets
Tissue collection
The study population consisted of consecutive patients admitted to St. George's Hospital for elective coronary artery bypass surgery (CABG). The following patients were excluded: (1) patients with unstable angina and recent myocardial infarct; (2) patients with a history of chronic infection or inflammatory disease, e.g. Crohn's disease, systemic lupus erythematous; (3) patients on steroids; (4) patients requiring redo surgery; and (5) patients requiring more than one procedure, e.g. CABG plus
Progenitor cells in neointimal lesions
We determined whether cells expressing progenitor cell markers exist in human atherosclerotic vessels. Human vascular samples with visible fatty streak lesions were assessed. Immunofluorescence was used to detect cells expressing progenitor cell markers CD34, VEGFR2, Sca-1, c-kit and CD133. Cells were identified within neointimal lesions which expressed CD34, VEGFR2, Sca-1 and c-kit (Fig. 1a–d). No cells expressing CD133 were detected in any sample (Fig. 1e).
Quantification of progenitor cells in lesions
To determine the number of
Discussion
There is growing evidence for the role of circulating progenitor cells in cardiovascular disease as recently reviewed by Roberts et al. [16]. We have previously shown the potential for non-bone marrow-derived circulating progenitor cells to contribute to vein graft arteriosclerosis [8], [17]. We have also shown that circulating progenitor cells have a role in endothelial repair [6], [9]. More recently, we presented data that abundant progenitor cells in the adventitia contribute to
Acknowledgements
This work was supported by Grants from the British Heart Foundation (PG/04/08) and Oak Foundation.
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Presented in part at the Scientific Sessions of the American Heart Association in New Orleans, 7–10 November 2004, and published in abstract form in Circulation 2004;110:176