Editorials
Fountain of Youth in the Aorta
2015 年 79 巻 7 号 p. 1439-1440
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2015 年 79 巻 7 号 p. 1439-1440
Tales of longevity, eternal life and rejuvenation are everywhere in the world. This is, I think, partly because ageing is associated with a number of diseases, including cardiovascular, metabolic and neurological diseases. Discoveries of stem cells, including embryonic stem cells (ES cells) and induced pluripotent stem cells (iPS cells), have ignited an enthusiasm for regenerative medicine to repair the dysfunctional tissues or organs from such diseases. In a sense, these stem cells can be regarded as a modern form of the fountain of youth.
Article p 1460
In parallel with the research on ES and iPS cells, researchers have discovered that adult bone marrow contains a rare population of cells that have the capacity of self-renewal and differentiation into multiple lineages of cells, and termed them “adult” or “mesenchymal” stem cells.1 It turns out that adult tissues other than bone marrow also contain cells with similar capacity to differentiate into multiple lineages of cells. Because these cells are heterogeneous for the capacity of differentiation and self-renewal, “mesenchymal stromal cells (MSC)” instead of mesenchymal stem cells has been proposed as an alternative term. In addition to their multipotent differentiation, MSCs seem to have the ability to directly modulate the function of many immune cells to suppress excessive inflammation.1 Because of this ability, intensive studies are ongoing to evaluate the therapeutic potential of MSCs for diseases such as inflammatory bowel diseases and autoimmune diseases.
Recently, a series of studies reported the therapeutic potential of MSCs in abdominal aortic aneurysm (AAA),2–5 and in this issue of the Journal, Ciavarella et al6 report that human aortic tissue contains MSCs. Prompted by the fact that AAA is a chronic inflammatory disease7 and MSCs show a plasticity between anti- and pro-inflammatory phenotypes, the authors asked if MSCs show different phenotypes depending on their origins. The answer was yes (Figure). MSCs from control aorta (control-MSCs) expressed negligible amounts of matrix metalloproteinase (MMP)-9 and showed the ability to suppress proliferation of peripheral blood mononuclear cells (PBMCs). In contrast, MSCs from AAA tissue (AAA-MSCs) showed higher expression of MMP-9 and failed to suppress the proliferation of PBMCs. Therefore, control-MSCs seem to have the ability to keep the proinflammatory response in check, whereas AAA-MSCs may contribute to the inflammatory status in AAA not only by a faulty anti-inflammatory property but also by serving as a source of MMP-9 themselves. Intriguingly, control-MSCs suppressed the expression of MMP-9 by AAA-MSCs in a coculture experiment. The authors suggest that such an alteration of the immunomodulatory function of MSCs may be involved in AAA pathogenesis, and restoration of the immunomodulatory function of MSCs may be a promising therapeutic strategy.
Mesenchymal stromal cells (MSCs) from a control aorta show the capacity to suppress immune cells. MSCs from AAA tissue show much weaker suppression of immune cells and secrete MMP-9, which may promote AAA progression. When cocultured, control MSCs can suppress MMP-9 secretion from AAA-MSCs. AAA, abdominal aortic aneurysm; MMP, matrix metalloproteinase.
This report by Ciavarella et al provokes a number of interesting questions and future research. I will discuss the nature of MSCs in the aorta, the immunomodulatory function of MSCs and the therapeutic potential of MSCs in AAA. The definition of MSCs is operational in that it relies on culturing the cells after isolation from various tissues.1 MSCs are defined as cells that can adhere to plastic plates and have a high capacity of proliferation to make multilineage cell populations. To better define MSCs, a phenotypic characterization has been proposed by the International Society for Cellular Therapy: positive for CD73, CD90, CD105 and negative for CD11b, CD14, CD34, CD45, CD79a and HLA-DR.8 The nature of MSCs derived from aortic tissue would be worth further investigation, including their molecular markers, self-renewability and differentiation capacity to make multiple lineages of cells. The difference between control-MSCs and AAA-MSCs is of interest. It is possible that control-MSCs and AAA-MSCs are entirely different populations. However, it is likely that they are similar, if not the same, populations because it is well established that the immunomodulatory function of MSCs is highly plastic in vitro. MSCs are usually suppressive to inflammation. However, when stimulated through pattern-recognition receptors such as the toll-like receptor (TLR) family, MSCs can be reprogrammed to express proinflammatory molecules. Thus, it has been proposed that MSCs can be dichotomized into proinflammatory MSC1 and anti-inflammatory MSC2, in an analogous way to M1 and M2 macrophages.9 As TLR signaling has been shown to participate in AAA pathogenesis,10,11 it is likely that MSCs in AAA tissue are reprogrammed to become the proinflammatory MSC1.
It is currently an open question whether the observed proinflammatory phenotype of MSCs in AAA is the cause or consequence of the inflammatory environment of AAA, or whether MSCs are involved in the pathogenesis of AAA. Apart from these questions, MSCs represent an attractive therapeutic target. Theoretically, exogenous MSCs can be used to ameliorate the inflammation in AAA by suppressing the infiltrating immune cells as well as the endogenous proinflammatory AAA-MSCs. Because cell-cell contact seems to be a prerequisite for the full activity of anti-inflammatory MSCs, delivery to the inflamed tissue would be essential for MSC-mediated therapy, which poses a serious challenge.12 Another attractive strategy is to reprogram endogenous AAA-MSCs to become anti-inflammatory MSC2, although reprogramming MSCs in vivo is another challenge. In this regard, it is noteworthy that coculture with control-MSCs suppressed the expression of MMP-9 by AAA-MSCs. It would be very interesting if suppression of MMP-9 is associated with the phenotypic change of AAA-MSCs toward the anti-inflammatory MSC2, which would provide conceptual evidence for the reprogrammability of AAA-MSCs.
Intensive research on AAA over the past decades has revealed that chronic inflammation plays a central role in its pathogenesis.13,14 The findings by Ciavarella et al provide another potential mechanism of the chronic inflammation in AAA involving MSCs. Hopefully we will some day be able to reprogram the proinflammatory MSCs in AAA tissue into the anti-inflammatory and tissue reparative MSCs that can rejuvenate the diseased aorta. Only future research will tell if we all have the fountain of youth in our aorta.
