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Lipid Boost Enhances Stem Cell-Mediated Cardiac Repair

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Review of “Pharmacological Elevation of Circulating Bioactive Phosphosphingolipids Enhances Myocardial Recovery after Acute Infarction” from Stem Cells Translational Medicine by Stuart P. Atkinson

Many strategies to promote cardiac regeneration following acute myocardial infarction (AMI) involve the transplantation of a variety of stem cells or stem cell derivatives. However, the inflammatory response to AMI also triggers a response which eventually mobilizes resident bone marrow stem/progenitor cells (BMSPCs) to undertake myocardial repair [1, 2].

Investigations into this response have highlighted a role for bioactive lipids (such as Sphingosine-1-phosphate (S1P) or Ceramide-1-phosphate (C1P)) [3, 4], and, therefore, many have hypothesized that pharmacological upregulation of these bioactive lipids could promote cardiac repair through enhanced stem cell mobilization. Now, researchers from the laboratory of Ahmed Abdel-Latif (University of Kentucky, USA) report on their studies into this proposed mechanism using a mouse model of AMI in the November edition of Stem Cells Translational Medicine [5].

To induce bioactive lipid levels in the blood, the researchers treated mice with tetrahydroxybutylimidazole (THI), an S1P lyase (SPL) inhibitor, 4 days after AMI. This time point avoids the averse inflammatory environment, and coincides with the optimal time at which stem cells home and proliferate before fibrosis and scar formation in the heart.

While AMI alone has the ability to induce S1P and C1P levels and bone marrow stem/progenitor cell (BMSPC) mobilization, THI treatment prolonged the effects to beyond 7 days, thereby enhancing any stem cell-mediated regenerative effects. The mobilized BMSPCs themselves expressed multiple genes related to stem cell mobilization and homing, angiogenesis, and cell survival, and the study correlated this to the significant recovery of cardiac function at 5 weeks after MI. This included the elevation of the ejection fraction, favorable remodeling of the left ventricle, a significant increase in the infarct wall and posterior wall thickness, and, importantly, a reduction in scar size.

But was this due to an increase in the homing of BMSPCs to the infarcted areas? Using GFP labeled BMSPCs, the study demonstrated that THI-treated mice had more than double the number of GFP+ cells specifically in the infarct border zone than the controls 5 weeks after MI. Further analysis also found a larger number of proliferative cardiomyocytes and c-Kit cells hematopoietic progenitors and an increase in capillary density (See adjoined figure - FITC-conjugated isolectin B4 labels capillaries). The authors did not, however, observe any evidence of transdifferentiation of BMSPCs into cardiac cells, so suggesting a potent paracrine mechanism.

So do we have a safe and effective means to promote heart regeneration following heart attack? A previous small human trial hinted that BMSPC mobilization after AMI may mediate improved cardiac recovery [6], and now this exciting study has shown that elevating the levels of bioactive lipids following inflammation can mobilize stem cells to effect heart repair. The authors also note that a THI analog, LX2931, is a safe and robust inhibitor of SPL already used in the treatment of rheumatoid arthritis [7], and they hope that future preclinical studies using these agents in will lead to a safe and effective treatment for heart attack-related myocardial damage.

References

  1. Hsieh PC, Segers VF, Davis ME, et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 2007;13:970-974.
  2. Abdel-Latif A, Zuba-Surma EK, Ziada KM, et al. Evidence of mobilization of pluripotent stem cells into peripheral blood of patients with myocardial ischemia. Exp Hematol 2010;38:1131-1142 e1131.
  3. Karapetyan AV, Klyachkin YM, Selim S, et al. Bioactive lipids and cationic antimicrobial peptides as new potential regulators for trafficking of bone marrow-derived stem cells in patients with acute myocardial infarction. Stem Cells Dev 2013;22:1645-1656.
  4. Ratajczak MZ, Lee H, Wysoczynski M, et al. Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex. Leukemia 2010;24:976-985.
  5. Klyachkin YM, Nagareddy PR, Ye S, et al. Pharmacological Elevation of Circulating Bioactive Phosphosphingolipids Enhances Myocardial Recovery After Acute Infarction. Stem Cells Transl Med 2015;4:1333-1343.
  6. Wyderka R, Wojakowski W, Jadczyk T, et al. Mobilization of CD34+CXCR4+ stem/progenitor cells and the parameters of left ventricular function and remodeling in 1-year follow-up of patients with acute myocardial infarction. Mediators Inflamm 2012;2012:564027.
  7. Bagdanoff JT, Donoviel MS, Nouraldeen A, et al. Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932). J Med Chem 2010;53:8650-8662.