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Atorvastatin Pretreatment Ameliorates Mesenchymal Stem Cell Migration through miR-146a/CXCR4 Signaling

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

BACKGROUND:

We previously found that atorvastatin (ATV) enhanced mesenchymal stem cells (MSCs) migration, by a yet unknown mechanism. CXC chemokine receptor 4 (CXCR4) is critical to cell migration and regulated by microRNA-146a (miR-146a). Therefore, this study aimed to assess whether ATV ameliorates MSCs migration through miR-146a/CXCR4 signaling.

METHODS:

Expression of CXCR4 was evaluated by flow cytometry. Expression of miR-146a was examined by reverse transcription-quantitative polymerase chain reaction. A transwell system was used to assess the migration ability of MSCs. Recruitment of systematically delivered MSCs to the infarcted heart was evaluated in Sprague–Dawley rats with acute myocardial infarction (AMI). Mimics of miR-146a were used in vitro, and miR-146a overexpression lentivirus was used in vivo, to assess the role of miR-146a in the migration ability of MSCs.

RESULTS:

The results showed that ATV pretreatment in vitro upregulated CXCR4 and induced MSCs migration. In addition, flow cytometry demonstrated that miR-146a mimics suppressed CXCR4, and ATV pretreatment no longer ameliorated MSCs migration because of decreased CXCR4. In the AMI model, miR-146a-overexpressing MSCs increased infarct size and fibrosis.

CONCLUSION:

The miR-146a/CXCR4 signaling pathway contributes to MSCs migration and homing induced by ATV pretreatment. miR-146a may be a novel therapeutic target for stimulating MSCs migration to the ischemic tissue for improved repair.

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References

  1. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation. 2012;126:551–68.

  2. Parizadeh SM, Jafarzadeh-Esfehani R, Ghandehari M, Parizadeh MR, Ferns GA, Avan A, et al. Stem cell therapy: a novel approach for myocardial infarction. J Cell Physiol. 2019;234:16904–12.

    Article  CAS  Google Scholar 

  3. Barzegar M, Kaur G, Gavins FNE, Wang Y, Boyer CJ, Alexander JS. Potential therapeutic roles of stem cells in ischemia-reperfusion injury. Stem Cell Res. 2019;37:101421.

    Article  CAS  Google Scholar 

  4. Samak M, Hinkel R. Stem cells in cardiovascular medicine: historical overview and future prospects. Cells. 2019;8:1530.

    Article  CAS  Google Scholar 

  5. Karantalis V, Hare JM. Use of mesenchymal stem cells for therapy of cardiac disease. Circ Res. 2015;116:1413–30.

    Article  CAS  Google Scholar 

  6. Narita T, Suzuki K. Bone marrow-derived mesenchymal stem cells for the treatment of heart failure. Heart Fail Rev. 2015;20:53–68.

    Article  CAS  Google Scholar 

  7. Miao C, Lei M, Hu W, Han S, Wang Q. A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction. Stem Cell Res Ther. 2017;8:242.

    Article  Google Scholar 

  8. Segers VF, Lee RT. Stem-cell therapy for cardiac disease. Nature. 2008;451:937–42.

    Article  CAS  Google Scholar 

  9. Luger D, Lipinski MJ, Westman PC, Glover DK, Dimastromatteo J, Frias JC, et al. Intravenously delivered mesenchymal stem cells: systemic anti-inflammatory effects improve left ventricular dysfunction in acute myocardial infarction and ischemic cardiomyopathy. Circ Res. 2017;120:1598–613.

    Article  CAS  Google Scholar 

  10. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89–118.

    Article  CAS  Google Scholar 

  11. Yang YJ, Qian HY, Huang J, Li JJ, Gao RL, Dou KF, et al. Combined therapy with simvastatin and bone marrow-derived mesenchymal stem cells increases benefits in infarcted swine hearts. Arterioscler Thromb Vasc Biol. 2009;29:2076–82.

    Article  Google Scholar 

  12. Tian XQ, Yang YJ, Li Q, Xu J, Huang PS, Xiong YY, et al. Combined therapy with atorvastatin and atorvastatin-pretreated mesenchymal stem cells enhances cardiac performance after acute myocardial infarction by activating SDF-1/CXCR4 axis. Am J Transl Res. 2019;11:4214–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gorabi AM, Kiaie N, Hajighasemi S, Banach M, Penson PE, Jamialahmadi T, et al. Statin-induced nitric oxide signaling: mechanisms and therapeutic implications. J Clin Med. 2019;8:2051.

    Article  CAS  Google Scholar 

  14. Assmus B, Urbich C, Aicher A, Hofmann WK, Haendeler J, Rössig L, et al. HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res. 2003;92:1049–55.

    Article  CAS  Google Scholar 

  15. Oikonomou E, Siasos G, Zaromitidou M, Hatzis G, Mourouzis K, Chrysohoou C, et al. Atorvastatin treatment improves endothelial function through endothelial progenitor cells mobilization in ischemic heart failure patients. Atherosclerosis. 2015;238:159–64.

    Article  CAS  Google Scholar 

  16. Dong Q, Yang Y, Song L, Qian H, Xu Z. Atorvastatin prevents mesenchymal stem cells from hypoxia and serum-free injury through activating AMP-activated protein kinase. Int J Cardiol. 2011;153:311–6.

    Article  Google Scholar 

  17. Yang YJ, Qian HY, Huang J, Geng YJ, Gao RL, Dou KF, et al. Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts. Eur Heart J. 2008;29:1578–90.

    Article  Google Scholar 

  18. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532–61.

    Article  CAS  Google Scholar 

  19. Schmidt-Lucke C, Fichtlscherer S, Rössig L, Kämper U, Dimmeler S. Improvement of endothelial damage and regeneration indexes in patients with coronary artery disease after 4 weeks of statin therapy. Atherosclerosis. 2010;211:249–54.

    Article  CAS  Google Scholar 

  20. Yang YJ, Qian HY, Song L, Geng YJ, Gao RL, Li N, et al. Strengthening effects of bone marrow mononuclear cells with intensive atorvastatin in acute myocardial infarction. Open Heart. 2020;7:e001139.

    Article  Google Scholar 

  21. Li N, Yang YJ, Qian HY, Li Q, Zhang Q, Li XD, et al. Intravenous administration of atorvastatin-pretreated mesenchymal stem cells improves cardiac performance after acute myocardial infarction: role of CXCR4. Am J Transl Res. 2015;7:1058–70.

    PubMed  PubMed Central  Google Scholar 

  22. Labbaye C, Spinello I, Quaranta MT, Pelosi E, Pasquini L, Petrucci E, et al. A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis. Nat Cell Biol. 2008;10:788–801.

    Article  CAS  Google Scholar 

  23. Wang W, Zhang Y, Liu W, Xiao H, Zhang Q, Wang J, et al. LMP1-miR-146a-CXCR4 axis regulates cell proliferation, apoptosis and metastasis. Virus Res. 2019;270:197654.

    Article  CAS  Google Scholar 

  24. Xu H, Yang YJ, Qian HY, Tang YD, Wang H, Zhang Q. Rosuvastatin treatment activates JAK-STAT pathway and increases efficacy of allogeneic mesenchymal stem cell transplantation in infarcted hearts. Circ J. 2011;75:1476–85.

    Article  CAS  Google Scholar 

  25. Müller-Ehmsen J, Peterson KL, Kedes L, Whittaker P, Dow JS, Long TI, et al. Rebuilding a damaged heart: long-term survival of transplanted neonatal rat cardiomyocytes after myocardial infarction and effect on cardiac function. Circulation. 2002;105:1720–6.

    Article  Google Scholar 

  26. Nigro P, Bassetti B, Cavallotti L, Catto V, Carbucicchio C, Pompilio G. Cell therapy for heart disease after 15 years: Unmet expectations. Pharmacol Res. 2018;127:77–91.

    Article  Google Scholar 

  27. Xu X, Zhu F, Zhang M, Zeng D, Luo D, Liu G, et al. Stromal cell-derived factor-1 enhances wound healing through recruiting bone marrow-derived mesenchymal stem cells to the wound area and promoting neovascularization. Cells Tissues Organs. 2013;197:103–13.

    Article  CAS  Google Scholar 

  28. Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, et al. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009;60:813–23.

    Article  CAS  Google Scholar 

  29. Song YL, Jiang H, Jiang NG, Jin YM, Zeng TT. Mesenchymal stem cell-platelet aggregates increased in the peripheral blood of patients with acute myocardial infarction and might depend on the stromal cell-derived factor 1/CXCR4 Axis. Stem Cells Dev. 2019;28:1607–19.

    Article  CAS  Google Scholar 

  30. Ma J, Ge J, Zhang S, Sun A, Shen J, Chen L, et al. Time course of myocardial stromal cell-derived factor 1 expression and beneficial effects of intravenously administered bone marrow stem cells in rats with experimental myocardial infarction. Basic Res Cardiol. 2005;100:217–23.

    Article  CAS  Google Scholar 

  31. Ghadge SK, Mühlstedt S, Ozcelik C, Bader M. SDF-1alpha as a therapeutic stem cell homing factor in myocardial infarction. Pharmacol Ther. 2011;129:97–108.

    Article  CAS  Google Scholar 

  32. Wynn RF, Hart CA, Corradi-Perini C, O'Neill L, Evans CA, Wraith JE, et al. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood. 2004;104:2643–5.

    Article  CAS  Google Scholar 

  33. Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells. 2006;24:1030–41.

  34. Cheng Z, Ou L, Zhou X, Li F, Jia X, Zhang Y, et al. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. Mol Ther. 2008;16:571–9.

  35. Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, Xu M, et al. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. J Mol Cell Cardiol. 2008;44:281–92.

  36. Xie J, Wang H, Song T, Wang Z, Li F, Ma J, et al. Tanshinone IIA and astragaloside IV promote the migration of mesenchymal stem cells by up-regulation of CXCR4. Protoplasma. 2013;250:521–30.

  37. Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ Res. 2017;120:229–43.

    Article  CAS  Google Scholar 

  38. Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3–11.

    Article  CAS  Google Scholar 

  39. Schaefer EJ, McNamara JR, Tayler T, Daly JA, Gleason JL, Seman LJ, et al. Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects. Am J Cardiol. 2004;93:31–9.

  40. Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation. 2004;110:1933–9.

  41. Song L, Yang YJ, Dong QT, Qian HY, Gao RL, Qiao SB, et al. Atorvastatin enhance efficacy of mesenchymal stem cells treatment for swine myocardial infarction via activation of nitric oxide synthase. PLoS One. 2013;8:e65702.

  42. Leone AM, Rutella S, Bonanno G, Abbate A, Rebuzzi AG, Giovannini S, et al. Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function. Eur Heart J. 2005;26:1196–204.

  43. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504.

  44. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

    Article  CAS  Google Scholar 

  45. Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nat Rev Mol Cell Biol. 2009;10:116–25.

    Article  CAS  Google Scholar 

  46. Kartha RV, Subramanian S. MicroRNAs in cardiovascular diseases: biology and potential clinical applications. J Cardiovasc Transl Res. 2010;3:256–70.

    Article  Google Scholar 

  47. Spinello I, Quaranta MT, Paolillo R, Pelosi E, Cerio AM, Saulle E, et al. Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy. Haematologica. 2015;100:1160–71.

  48. Quaranta MT, Olivetta E, Sanchez M, Spinello I, Paolillo R, Arenaccio C, et al. miR-146a controls CXCR4 expression in a pathway that involves PLZF and can be used to inhibit HIV-1 infection of CD4(+) T lymphocytes. Virology. 2015;478:27–38.

  49. Spinello I, Quaranta MT, Riccioni R, Riti V, Pasquini L, Boe A, et al. MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias. Blood Cancer J. 2011;1:e26.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81500270 and 81700299).

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Authors and Affiliations

  1. Beijing Key Laboratory of Hypertension, Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Gongti South Road, No. 8, Beijing, 100020, China

    Na Li & Jian Zhou

  2. Department of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Diseases, Capital Medical University, Beijing, 100029, China

    Xue-Yuan Guo & Xian-Liang Yan

  3. Department of Radiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China

    Fang-Fang Yu

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  1. Na Li
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Correspondence to Na Li.

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The animal studies were performed after receiving approval from the Care of Experimental Animals Committee of Beijing Chaoyang Hospital (Approval No. 2020-Animal-271).

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Li, N., Guo, XY., Zhou, J. et al. Atorvastatin Pretreatment Ameliorates Mesenchymal Stem Cell Migration through miR-146a/CXCR4 Signaling. Tissue Eng Regen Med 18, 863–873 (2021). https://doi.org/10.1007/s13770-021-00362-z

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  • DOI: https://doi.org/10.1007/s13770-021-00362-z

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