Response to Letter Regarding Article, “Smooth Muscle Cells Healing Atherosclerotic Plaque Disruptions Are of Local, Not Blood, Origin in Apolipoprotein E Knockout Mice”
We welcome critical review of our work1 by colleagues. Indeed, far too few discussions are raised within the field of vascular progenitor cell biology, and this is part of the reason that a number of poorly documented theories in recent years have become unsubstantiated dogma. In the following letter, we have addressed each of the concerns raised by Hibbert et al, and as we hope to make clear, we respectfully disagree with each of them.
First, Hibbert et al question whether hematopoietic stem cells of the bone marrow–transplanted mice in our long-term atherosclerosis study remained of donor origin, and they cite an article by Szilvassy et al2 to argue that this may not have been the case. In that article, however, the repopulating ability of the bone marrow graft was compromised by repeated serial transplantations, an approach which has absolutely no bearing on our study. We used a high dose of normal bone marrow cells and, indeed, we have previously shown that our protocol yields long-term engraftment of hematopoietic stem cells.3 Long-term engraftment was also confirmed in our experiment1 by the presence of donor-type macrophage foam cells (Figure 3a in our article) and platelets (data not shown) at postmortem examination.
Second, we agree that our surgical procedure could have caused intraplaque hypoxia, but because plaque healing is a local process in the superficial, oxygenated part of the plaque, we find it unlikely that this would influence the results.
Third, our work is not in conflict with the studies of Hillebrands et al and others,4 who demonstrated that smooth muscle cells (SMCs) in allograft vasculopathy are of recipient origin when no immunosuppression is applied. We do, however, disagree with the interpretation of these data by some investigators as proof that SMCs can be derived from circulating progenitor cells. The more straightforward explanation is that medial SMCs (or possibly other vessel wall cells) migrate into the allograft from the contiguous recipient vasculature, and this possibility has yet to be ruled out.
Finally, SMC proliferation does occur in atherosclerosis, and the shortening of telomeres indicates that advanced plaque SMCs may have undergone from 7 to 13 population doublings during atherogenesis (equivalent to a population expansion of 128 to 8192-fold).5 Therefore, undoubtedly, SMC proliferation could account for the number of SMCs observed in atherosclerotic plaques. Incidentally, on this point we seem to agree with a previous article from O’Brien and colleagues.6
In conclusion, we thank Hibbert et al for their comments, but we remain convinced that the only reasonable explanation for the lack of circulating progenitor cell contribution to plaque SMCs in our experiments is the simplest possible: that it does not occur.
Bentzon JF, Sondergaard CS, Kassem M, Falk E. Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice. Circulation. 2007; 116: 2053–2061.
Szilvassy SJ, Humphries RK, Lansdorp PM, Eaves AC, Eaves CJ. Quantitative assay for totipotent reconstituting hematopoietic stem cells by a competitive repopulation strategy. Proc Natl Acad Sci U S A. 1990; 87: 8736–8740.
Bentzon JF, Weile C, Sondergaard CS, Hindkjaer J, Kassem M, Falk E. Smooth muscle cells in atherosclerosis originate from the local vessel wall and not circulating progenitor cells in apoE knockout mice. Arterioscler Thromb Vasc Biol. 2006; 26: 2696–2702.
Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A, Goddard M, Bennett M. Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ Res. 2006; 99: 156–164.
O’Brien ER, Alpers CE, Stewart DK, Ferguson M, Tran N, Gordon D, Benditt EP, Hinohara T, Simpson JB, and Schwartz SM. Proliferation in primary and restenotic coronary atherectomy tissue: implications for antiproliferative therapy. Circ Res. 1993; 73: 223–231.