Differentiation of the endoderm into organ-specific types of epithelium depends on the interaction of epithelial cells with organ-specific mural cells and their matrix — By analogy, it seems possible that different mural cells and intimal cells control the phenotype of overlying endothelium. Conversely, differences in lineage within the endothelium might control the formation of intimal cell masses Such cell type interaction-specific interactions between epithelium and mesenchyme might explain the localization of atherosclerosis at specific sites.
The media is not the only possible source for intimal cells. Studies using labeled bone marrow cells in mice and humans have purported to show that intimal SMCs in atherosclerotic plaques could be derived from circulating marrow-derived cells , These studies, however, have not held up to more careful work 8 , 47 , A more likely source is the adventitia.
The adventitia of arteries is defined as those cells outside the external elastic lamina Figure 8. This layer contains endothelial cells, neurons, blood-derived macrophages, lymphocytes, mast cells, and fibroblasts. Recent studies show that adventitial fibroblasts include cells identified as stem-like by the expression of markers like c-kit and sca1 Cell tracing studies show that adventitial cells can cross the media of injured vessels to form a neointima , , Moreover, transplantation studies in vivo show that adventitial stem cells applied to the outside of an injured vessel can migrate across the media and form an intima The intima is a layer of connective tissue located between the endothelium and a layer of elastin called the internal elastic lamina.
The media is delimited by the dashed black lines representing the internal elastic lamina and the external elastic lamina EEL. Only rare cells, including lymphocytes and smooth muscle cells, are seen in the normal intima of the small mammals usually used to study atherosclerosis. However, in humans, intimal cells accumulate spontaneously during normal development and appear as a clone in the atherosclerotic lesions of adult humans.
Based on immunocytochemistry, these cells are usually considered to be smooth muscle cells. In fat-fed animals, including humans, lipid accumulates in the intima to form the characteristic fatty atherosclerotic lesion. The outer limit of the tunica media is also defined by a layer of elastin called the EEL. Extrinsic to the EEL is a poorly defined tissue that is part of the matrix surrounding not just blood vessels but the parenchymal cells that comprise organs. The part of this matrix close to the vessel wall is called the adventitia.
Adventitial fibroblasts are also of interest because of their relationship to fibrotic responses. Myofibroblasts characterize scleroderma and may be derived from vessel wall cells Curiously, no effort has been reported to use cluster analysis to compare myofibroblasts with intimal cells. The origin of intimal cells from adventitial cells may imply that intimal cells are of a different cell type than medial cells. Tallquist et al.
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This differentiation occurs when epicardial cells lose the expression of a transcription factor, Tcf The Tcfnegative cells undergo epithelial—mesenchymal transformation, migrate to coat the nascent endothelial tubes, and form mural cells. These mural cells initially have the properties of pericytes and populate the entire coronary microvasculature In contrast, the fibroblasts around these vessels, that is the adventitial cells, originate from the Tcfpositive epicardial cells by migration Presumably the adventitial cells express smooth muscle actin only during cardiac fibrosis when they become myofibroblasts.
The observations of Tallquist et al. Much less is known about the origin of adventitial cells other than those in the heart , , , Both arise from the epicardium, but the smooth muscle lineage requires first the loss of expression of Tcf Presumably, the intimal cells arise from the medial smooth muscle but, as discussed in the text, we cannot rule out origin from the adventitia, especially since adventitial fibroblasts are the source of smooth muscle actin-rich myofibroblasts seen in injured myocardium.
There is, finally, one additional possible source for intimal cells, the endothelium. Endothelial cells are capable of undergoing EMT , — EMT has been intensively studied in the formation of the cells making up the cardiac valves , , , In addition, Karsan et al. This labeled cell differentiates into smooth muscle.
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Endothelial cells that also showed the canonical VE cadherin marker, however, did not differentiate into smooth muscle It is intriguing to wonder if the normal intima might originate in such a peculiar precursor cell. The origin of the intimal cells of the human coronary artery from a human cell equivalent to the Tcfpositive epicardial cells of Tallquist et al. Figure 10 proposes perhaps the simplest model for plaque monoclonality. In this model, rare mural cells are trapped within the intima as the internal elastica forms and the fenestrae, holes in the internal elastic lamina, shrink , As discussed in the text, intimal smooth muscle cells in adult human atherosclerosis are clonal.
Although we do not know that this clone is derived from intimal clones present at birth, this is an obvious hypothesis. The next question might be how would normal intima develop as a clone? The simplest hypothesis is that some mural cells that coat the arterial endothelium get trapped within the forming internal elastica. Isolated from other mural cells, these intimal cells would develop a phenotype dependent on both their lineage and the conditions of being confined between the endothelium and the internal elastic lamina.
A simple alternative is that migration from the media is limited not only by the number and size of passageways across the internal elastic lamella but also by secretory and cytoskeletal changes required for transfenestral migration. Fetal properties that allow some medial cells to migrate may be developmental but could be reactivated in a subset of the medial SMCs when arterial injuries occur. A recent study by Lu et al. Finally, localization of intimal cells might be the result of stimuli coming from endothelial cells responding to flow or from subsets of endothelial cells with their own lineages Figure 10 does not rule out the possibility that the clone selected for growth in the intima has special properties derived from its developmental lineage, acquired because of the environment of an injured media, or resulting from mutation.
We do not know whether the origin of a lesion in clones of intimal cells is important to the natural history of the plaques. The common belief is that atherosclerotic lesions develop selectively in areas where the arterial endothelium is exposed to turbulent blood flow However, as already discussed, we know that the neointimas formed after injury predispose to atherosclerosis and that sites with similar rheology may or may not develop atherosclerosis.
Therefore, it seems likely that spontaneous and intimal masses may be the initial cause of atherosclerosis in humans. Moreover, sites that show spontaneous intimal thickening 26 , are also sites that manifest in later life as lesions that rupture, leading to occlusion and thromboembolic events. Even though carcinogens can promote the growth of intimal cell masses 21 , there is as yet no evidence that the clonal growth of the human plaque is due to a mutation. Perhaps such evidence will emerge with applications of next-generation sequencing to detect mutations in the plaque cells Intimal cell masses in human arteries precede atherosclerosis.
However, we do not know that these masses are clonal. It is conceivable that clonality develops later as lesions develop as is seen in mice responding to arterial injury. Intimal cells may determine where plaques develop. It is possible that intimal cells control the phenotype of overlying endothelium, including properties that attract leukocytes leading to the development of atherosclerotic lesions. Intimal cells may also provide an environment that accumulates toxic products of lipids. Intimal cells have properties distinct from our traditional view of SMCs.
Cluster analysis, combined with lineage tracking, has opened a new frontier in defining cell types within the intima. It will be important to use these methods to define the cell types comprising the atherosclerotic clone. The extent of intimal cell masses across the normal human arterial tree of children is not known. There has been no thorough study of the arterial intima in the arterial tree of human children or other large mammals. Such masses may also occur later in life and lead to the development of new atherosclerotic lesions as suggested by DeBakey and Glaeser Differences between models of atherosclerosis in mice versus the disease in humans may reflect the fact that mice lack intimal cells.
Intimal cell masses, probably clonal in origin, may provide a soil for lesions that are distinct from those in the mouse model systems. Mark W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. F Faculty Reviews are written by members of the prestigious F Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Alongside their report, reviewers assign a status to the article:.
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Get PDF. Get XML. How to cite this article. NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details. An update on clonality: what smooth muscle cell type makes up the atherosclerotic plaque?
Almost 50 years ago, Earl Benditt and his son John described the clonality of the atherosclerotic plaque. This led Benditt to propose that the atherosclerotic lesion was a smooth muscle neoplasm, similar to the leiomyomata seen in the uterus of most women. Although the observation of clonality has been confirmed many times, interest in the idea that atherosclerosis might be a form of neoplasia waned because of the clinical success of treatments for hyperlipemia and because animal models have made great progress in understanding how lipid accumulates in the plaque and may lead to plaque rupture.
First, we now know that clonality is a property of normal tissue development. Second, this is even true in the vessel wall, where we now know that formation of clonal patches in that wall is part of the development of smooth muscle cells that make up the tunica media of arteries. Keywords Atherosclerosis, smooth muscle cells, developmental biology, vascular biology, clonality, somatic mosaicism, endothelium.
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