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Moderating Atherosclerosis with Mesenchymal Stem Cells?

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Review “Mesenchymal Stem Cells Ameliorate Atherosclerotic Lesions via Restoring Endothelial Function” from Stem Cells TM by Stuart P. Atkinson

Multiple studies link mesenchymal stem cell (MSC) transplants/transfusions to the amelioration of vascular diseases and disorders, such as injuries of the heart [1] and hind limb ischemia [2]. However, no study has yet assessed their therapeutic role in atherosclerosis; a vascular disorder involving damaging changes to the inner walls of blood vessels. Now, in a new study from Shih-Chieh Hung (Taipei Veterans General Hospital) and Guei-Jane Wang (China Medical University), researchers have utilized in vitro and in vivo models to study the key therapeutic factors and mechanisms that human and mouse MSCs can provide in treating atherosclerosis-induced changes [3].

Endothelial cell dysfunction is one of the earliest changes associated with atherosclerosis [4], and the group first assessed the ability of damaged endothelial cells to recruit hMSCs. This in vitro assay used oxidized low-density lipoprotein (oxLDL)-treated human umbilical vein endothelial cells (HUVECs) [5] which promotes endothelial cell dysfunction through the suppression of phospho-Akt, phospho-endothelial NOS (eNOS) and total eNOS levels [6]. hMSCs migrated in greater numbers to the oxLDL-treated endothelial cells than control cells, in line with an increase in the MSC chemokine SDF-1. Blocking this chemokine, or its receptor CXCR4, reduced migration, suggesting that hMSC-recruitment by HUVECs relies on the SDF-1-CXCR4 axis. Further studies found that indirect co-culture of MSCs protected against oxLDL-induced changes in HUVECs, in correlation with an observed increase in secreted Interleukin 8 (IL8) levels from hMSCs. IL8 is a chemokine produced by macrophages and endothelial cells with roles in chemotaxis and angiogenesis. IL8 alone could partly substitute for hMSCs in the co-culture experiment, and addition of IL8-neutralizing antibodies reduced the effect of hMSC addition. The researchers also uncovered an important role for the mitogen-activated protein kinase (MAPK) signaling pathway in the secretion of IL8 by hMSCs.

The research then moved to a mouse model of atherosclerosis (apolipoprotein E-deficient [apoE-/-] mice fed a high-fat diet for 5 weeks). While mMSC transfusion did not change blood lipid levels, it did improve endothelium-dependent vasodilatation, decreased the aortic plaque burden (See Figure – Representative atherosclerotic lesions are red in color), and increased the levels of Akt/eNOS phosphorylation in the aortic endothelium. MIP-2, the IL8 homolog in mice, was also increased in oxLDL-treated mMSCs, and pre-treating mMSCs with a neutralizing MIP-2 antibody reduced the ameliorative effect of mMSCs after transfusion. Indeed MIP-2 injection alone was able to improve endothelium-dependent vasodilatation and increased phospho-Akt+ and phospho-eNOS+ levels in aortic endothelium, but did not alter the aortic plaque burden.

The overall findings of this research are that MSCs can play a role in alleviating atherosclerotic effects, most likely through a paracrine effect mediated by IL8 and the p38/MAPK signaling pathway. Although further studies are required, this study should provide a solid framework for future research and provides druggable targets for the treatment of this unfortunately prevalent disorder.

References

  1. Nagaya N, Fujii T, Iwase T, et al. Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am J Physiol Heart Circ Physiol 2004;287:H2670-2676.
  2. Huang WH, Chen HL, Huang PH, et al. Hypoxic mesenchymal stem cells engraft and ameliorate limb ischaemia in allogeneic recipients. Cardiovascular research 2014;101:266-276.
  3. Lin YL, Yet SF, Hsu YT, et al. Mesenchymal Stem Cells Ameliorate Atherosclerotic Lesions via Restoring Endothelial Function. Stem Cells Translational Medicine 2015;4:44-55.
  4. Luscher TF and Barton M Biology of the endothelium. Clin Cardiol 1997;20:II-3-10.
  5. Witztum JL and Steinberg D Role of oxidized low density lipoprotein in atherogenesis. The Journal of clinical investigation 1991;88:1785-1792.
  6. Blair A, Shaul PW, Yuhanna IS, et al. Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. The Journal of biological chemistry 1999;274:32512-32519.