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Transplantation of Umbilical Cord-Derived Mesenchymal Stem Cells Overexpressing Lipocalin 2 Ameliorates Ischemia-Induced Injury and Reduces Apoptotic Death in a Rat Acute Myocardial Infarction Model

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Abstract

Myocardial infarction (MI) is a leading cause of death worldwide and requires development of efficient therapeutic strategies . Mesenchymal stem cells (MSCs) -based therapy of MI has been promising but inefficient due to undesirable microenvironment of the infarct tissue. Hence, the current study was conducted to fortify MSCs against the unfavorable microenvironment of infarct tissue via overexpression of Lipocalin 2 (Lcn2) as a cytoprotective factor. The engineered cells (Lcn2-MSCs) were transplanted to infarcted heart of a rat model of MI. According to our findings, Lcn2 overexpression resulted in increased MSCs survival in the MI tissue (p < 0.05) compared to non-engineered cells. Furthermore, the infusion of Lcn2-MSCs mitigated Left ventricle (LV) remodeling, decreased fibrosis (p < 0.0001), and reduced apoptotic death of the LVs’ cells (p < 0.0001) compared to the control. Our findings suggest a potential novel therapeutic strategy for MI, however, further investigations such as safety and efficacy assessments in large animals followed by clinical trials are required.

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References

  1. Sutton, M. G. S. J., & Sharpe, N. (2000). Left ventricular remodeling after myocardial infarction: Pathophysiology and therapy. Circulation, 101(25), 2981–2988.

    CAS  PubMed  Google Scholar 

  2. Bergmann, O., Bhardwaj, R. D., Bernard, S., Zdunek, S., Barnabé-Heider, F., Walsh, S., Zupicich, J., Alkass, K., Buchholz, B. A., Druid, H., Jovinge, S., & Frisén, J. (2009). Evidence for cardiomyocyte renewal in humans. Science, 324(5923), 98–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Garbern, J. C., & Lee, R. T. (2013). Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell, 12(6), 689–698.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Fisher, S. A., Doree, C., Mathur, A., & Martin-Rendon, E. (2015). Meta-analysis of cell therapy trials for patients with heart failure. Circulation Research, 116(8), 1361–1377.

    CAS  PubMed  Google Scholar 

  5. Behfar, A., Crespo-Diaz, R., Terzic, A., & Gersh, B. J. (2014). Cell therapy for cardiac repair—Lessons from clinical trials. Nature Reviews Cardiology, 11(4), 232–246.

    PubMed  Google Scholar 

  6. Williams, A. R., & Hare, J. M. (2011). Mesenchymal stem cells: Biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circulation Research, 109(8), 923–940.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Amiri, F., Jahanian-Najafabadi, A., & Roudkenar, M. H. (2015). In vitro augmentation of mesenchymal stem cells viability in stressful microenvironments. Cell Stress and Chaperones, 20(2), 237–251.

    CAS  PubMed  Google Scholar 

  8. Choi, Y.-H., Kurtz, A., & Stamm, C. (2011). Mesenchymal stem cells for cardiac cell therapy. Human Gene Therapy, 22(1), 3–17.

    CAS  PubMed  Google Scholar 

  9. Liang, X., Ding, Y., Zhang, Y., Chai, Y., He, J., Chiu, S., et al. (2015). Activation of NRG1-ERBB4 signaling potentiates mesenchymal stem cell-mediated myocardial repairs following myocardial infarction. Cell Death & Disease, 6(5), e1765–e1765.

    CAS  Google Scholar 

  10. Zhang, Y., Liao, S., Yang, M., Liang, X., Poon, M.-W., Wong, C.-Y., Wang, J., Zhou, Z., Cheong, S. K., Lee, C. N., Tse, H. F., & Lian, Q. (2012). Improved cell survival and paracrine capacity of human embryonic stem cell-derived mesenchymal stem cells promote therapeutic potential for pulmonary arterial hypertension. Cell Transplantation, 21(10), 2225–2239.

    PubMed  Google Scholar 

  11. Singh, A., Singh, A., & Sen, D. (2016). Mesenchymal stem cells in cardiac regeneration: A detailed progress report of the last 6 years (2010–2015). Stem Cell Research & Therapy, 7(1), 82.

    Google Scholar 

  12. Majka, M., Sułkowski, M., Badyra, B., & Musiałek, P. (2017). Concise review: Mesenchymal stem cells in cardiovascular regeneration: Emerging research directions and clinical applications. Stem Cells Translational Medicine, 6(10), 1859–1867.

    PubMed  PubMed Central  Google Scholar 

  13. Caplan, A. I., & Dennis, J. E. (2006). Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry, 98(5), 1076–1084.

    CAS  PubMed  Google Scholar 

  14. Ball, S. G., Shuttleworth, C. A., & Kielty, C. M. (2007). Mesenchymal stem cells and neovascularization: Role of platelet-derived growth factor receptors. Journal of Cellular and Molecular Medicine, 11(5), 1012–1030.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Valle-Prieto, A., & Conget, P. A. (2010). Human mesenchymal stem cells efficiently manage oxidative stress. Stem Cells and Development, 19(12), 1885–1893.

    CAS  PubMed  Google Scholar 

  16. Choe, G., Kim, S.-W., Park, J., Park, J., Kim, S., Kim, Y. S., Ahn, Y., Jung, D. W., Williams, D. R., & Lee, J. Y. (2019). Anti-oxidant activity reinforced reduced graphene oxide/alginate microgels: Mesenchymal stem cell encapsulation and regeneration of infarcted hearts. Biomaterials, 225, 119513.

    CAS  PubMed  Google Scholar 

  17. Uccelli, A., & Prockop, D. J. (2010). Why should mesenchymal stem cells (MSCs) cure autoimmune diseases? Current Opinion in Immunology, 22(6), 768–774.

    CAS  PubMed  Google Scholar 

  18. Toma, C., Pittenger, M. F., Cahill, K. S., Byrne, B. J., & Kessler, P. D. (2002). Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation, 105(1), 93–98.

    PubMed  Google Scholar 

  19. Mohammadzadeh, M., Halabian, R., Gharehbaghian, A., Amirizadeh, N., Jahanian-Najafabadi, A., Roushandeh, A. M., & Roudkenar, M. H. (2012). Nrf-2 overexpression in mesenchymal stem cells reduces oxidative stress-induced apoptosis and cytotoxicity. Cell Stress and Chaperones, 17(5), 553–565.

    CAS  PubMed  Google Scholar 

  20. Hao, T., Li, J., Yao, F., Dong, D., Wang, Y., Yang, B., & Wang, C. (2017). Injectable fullerenol/alginate hydrogel for suppression of oxidative stress damage in brown adipose-derived stem cells and cardiac repair. ACS Nano, 11(6), 5474–5488.

    CAS  PubMed  Google Scholar 

  21. Li, X.,Tamama, K.,Xie, X., & Guan, J. (2016). Improving cell engraftment in cardiac stem cell therapy. Stem cells international, 2016.

  22. Halabian, R., Tehrani, H. A., Jahanian-Najafabadi, A., & Roudkenar, M. H. (2013). Lipocalin-2-mediated upregulation of various antioxidants and growth factors protects bone marrow-derived mesenchymal stem cells against unfavorable microenvironments. Cell Stress and Chaperones, 18(6), 785–800.

    CAS  PubMed  Google Scholar 

  23. Garcia-Castro, J., Trigueros, C., Madrenas, J., Perez-Simon, J., Rodriguez, R., & Menendez, P. (2008). Mesenchymal stem cells and their use as cell replacement therapy and disease modelling tool. Journal of Cellular and Molecular Medicine, 12(6b), 2552–2565.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Xie, X., Sun, A., Zhu, W., Huang, Z., Hu, X., Jia, J., Zou, Y., & Ge, J. (2012). Transplantation of mesenchymal stem cells preconditioned with hydrogen sulfide enhances repair of myocardial infarction in rats. The Tohoku Journal of Experimental Medicine, 226(1), 29–36.

    CAS  PubMed  Google Scholar 

  25. Sadeghi, F., Etebari, M., Roudkenar, M. H., & Jahanian-Najafabadi, A. (2018). Lipocalin2 protects human embryonic kidney cells against Cisplatin–induced Genotoxicity. Iranian journal of pharmaceutical research: IJPR, 17(1), 147–154.

    CAS  PubMed  Google Scholar 

  26. Roudkenar, M. H., Halabian, R., Tehrani, H. A., Amiri, F., Jahanian-Najafabadi, A., Roushandeh, A. M., Abbasi-Malati, Z., & kuwahara, Y. (2018). Lipocalin 2 enhances mesenchymal stem cell-based cell therapy in acute kidney injury rat model. Cytotechnology, 70(1), 103–117.

    CAS  PubMed  Google Scholar 

  27. Yndestad, A., Landrø, L., Ueland, T., Dahl, C. P., Flo, T. H., Vinge, L. E., et al. (2009). Increased systemic and myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and experimental heart failure. European Heart Journal, 30(10), 1229–1236.

    CAS  PubMed  Google Scholar 

  28. Amiri, F., Halabian, R., Salimian, M., Shokrgozar, M. A., Soleimani, M., Jahanian-Najafabadi, A., & Roudkenar, M. H. (2014). Induction of multipotency in umbilical cord-derived mesenchymal stem cells cultivated under suspension conditions. Cell Stress and Chaperones, 19(5), 657–666.

    CAS  PubMed  Google Scholar 

  29. Song, Y.-S., Joo, H.-W., Park, I.-H., Shen, G.-Y., Lee, Y., Shin, J. H., Kim, H., & Kim, K. S. (2017). Bone marrow mesenchymal stem cell-derived vascular endothelial growth factor attenuates cardiac apoptosis via regulation of cardiac miRNA-23a and miRNA-92a in a rat model of myocardial infarction. PLoS One, 12(6), e0179972.

    PubMed  PubMed Central  Google Scholar 

  30. Ruvinov, E., Leor, J., & Cohen, S. (2011). The promotion of myocardial repair by the sequential delivery of IGF-1 and HGF from an injectable alginate biomaterial in a model of acute myocardial infarction. Biomaterials, 32(2), 565–578.

    CAS  PubMed  Google Scholar 

  31. Chen, Y., Zuo, J., Chen, W., Yang, Z., Zhang, Y., Hua, F., et al. (2019). The enhanced effect and underlying mechanisms of mesenchymal stem cells with IL-33 overexpression on myocardial infarction. Stem Cell Research & Therapy, 10(1), 1–14.

    Google Scholar 

  32. Roudkenar, M. H., Halabian, R., Bahmani, P., Roushandeh, A. M., Kuwahara, Y., & Fukumoto, M. (2011). Neutrophil gelatinase-associated lipocalin: A new antioxidant that exerts its cytoprotective effect independent on Heme Oxygenase-1. Free Radical Research, 45(7), 810–819.

    CAS  PubMed  Google Scholar 

  33. Honczarenko, M., Le, Y., Swierkowski, M., Ghiran, I., Glodek, A. M., & Silberstein, L. E. (2006). Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells, 24(4), 1030–1041.

    CAS  PubMed  Google Scholar 

  34. Rombouts, W., & Ploemacher, R. (2003). Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia, 17(1), 160–170.

    CAS  PubMed  Google Scholar 

  35. Kolossov, E., Bostani, T., Roell, W., Breitbach, M., Pillekamp, F., Nygren, J. M., Sasse, P., Rubenchik, O., Fries, J. W. U., Wenzel, D., Geisen, C., Xia, Y., Lu, Z., Duan, Y., Kettenhofen, R., Jovinge, S., Bloch, W., Bohlen, H., Welz, A., Hescheler, J., Jacobsen, S. E., & Fleischmann, B. K. (2006). Engraftment of engineered ES cell–derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. The Journal of Experimental Medicine, 203(10), 2315–2327.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu, X.b., Jiang, J., Gui, C., Hu, X.y., Xiang, M.x., & Wang, J.a. (2008). Angiopoietin-1 protects mesenchymal stem cells against serum deprivation and hypoxia-induced apoptosis through the PI3K/Akt pathway 1. Acta Pharmacologica Sinica, 29(7), 815–822.

  37. Müller-Ehmsen, J., Krausgrill, B., Burst, V., Schenk, K., Neisen, U. C., Fries, J. W., et al. (2006). Effective engraftment but poor mid-term persistence of mononuclear and mesenchymal bone marrow cells in acute and chronic rat myocardial infarction. Journal of Molecular and Cellular Cardiology, 41(5), 876–884.

    PubMed  Google Scholar 

  38. Tong, Z., Chakraborty, S., Sung, B., Koolwal, P., Kaur, S., Aggarwal, B. B., Mani, S. A., Bresalier, R. S., Batra, S. K., & Guha, S. (2011). Epidermal growth factor down-regulates the expression of neutrophil gelatinase-associated lipocalin (NGAL) through E-cadherin in pancreatic cancer cells. Cancer, 117(11), 2408–2418.

    CAS  PubMed  Google Scholar 

  39. Li, W., Ma, N., Ong, L. L., Nesselmann, C., Klopsch, C., Ladilov, Y., Furlani, D., Piechaczek, C., Moebius, J. M., Lützow, K., Lendlein, A., Stamm, C., Li, R. K., & Steinhoff, G. (2007). Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells, 25(8), 2118–2127.

    CAS  PubMed  Google Scholar 

  40. Wang, X., Zhao, T., Huang, W., Wang, T., Qian, J., Xu, M., Kranias, E. G., Wang, Y., & Fan, G. C. (2009). Hsp20-engineered mesenchymal stem cells are resistant to oxidative stress via enhanced activation of Akt and increased secretion of growth factors. Stem Cells, 27(12), 3021–3031.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang, Z., Zhu, L., Feng, P., Tan, Y., Zhang, B., Gao, E., et al. (2019). C1q/tumor necrosis factor-related protein-3-engineered mesenchymal stromal cells attenuate cardiac impairment in mice with myocardial infarction. Cell Death & Disease, 10(7), 1–15.

    Google Scholar 

  42. Asanuma, H., Meldrum, D. R., & Meldrum, K. K. (2010). Therapeutic applications of mesenchymal stem cells to repair kidney injury. The Journal of Urology, 184(1), 26–33.

    PubMed  Google Scholar 

  43. Park, B.-W.,Jung, S.-H.,Das, S.,Lee, S. M.,Park, J.-H.,Kim, H., et al. (2020). In vivo priming of human mesenchymal stem cells with hepatocyte growth factor–engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair. Science Advances, 6(13), eaay6994.

  44. Yang, J., Zhou, W., Zheng, W., Ma, Y., Lin, L., Tang, T., Liu, J., Yu, J., Zhou, X., & Hu, J. (2007). Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction. Cardiology, 107(1), 17–29.

    PubMed  Google Scholar 

  45. Zhang, D., Fan, G.-C., Zhou, X., Zhao, T., Pasha, Z., Xu, M., Zhu, Y., Ashraf, M., & Wang, Y. (2008). Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. Journal of Molecular and Cellular Cardiology, 44(2), 281–292.

    CAS  PubMed  Google Scholar 

  46. Krijnen, P., Nijmeijer, R., Meijer, C., Visser, C., Hack, C., & Niessen, H. (2002). Apoptosis in myocardial ischaemia and infarction. Journal of Clinical Pathology, 55(11), 801–811.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hu, X., Yu, S. P., Fraser, J. L., Lu, Z., Ogle, M. E., Wang, J.-A., & Wei, L. (2008). Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. The Journal of Thoracic and Cardiovascular Surgery, 135(4), 799–808.

    CAS  PubMed  Google Scholar 

  48. Roudkenar, M. H., Halabian, R., Roushandeh, A. M., Nourani, M. R., Masroori, N., Ebrahimi, M., Nikogoftar, M., Rouhbakhsh, M., Bahmani, P., Najafabadi, A. J., & Shokrgozar, M. A. (2009). Lipocalin 2 regulation by thermal stresses: Protective role of Lcn2/NGAL against cold and heat stresses. Experimental Cell Research, 315(18), 3140–3151.

    CAS  PubMed  Google Scholar 

  49. Gnecchi, M., He, H., Liang, O. D., Melo, L. G., Morello, F., Mu, H., Noiseux, N., Zhang, L., Pratt, R. E., Ingwall, J. S., & Dzau, V. J. (2005). Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nature Medicine, 11(4), 367–368.

    CAS  PubMed  Google Scholar 

  50. Xu, G., Ahn, J., Chang, S., Eguchi, M., Ogier, A., Han, S., Park, Y. S., Shim, C. Y., Jang, Y. S., Yang, B., Xu, A., Wang, Y., & Sweeney, G. (2012). Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation. Journal of Biological Chemistry, 287(7), 4808–4817.

    CAS  PubMed  Google Scholar 

  51. Mishra, J., Dent, C., Tarabishi, R., Mitsnefes, M. M., Ma, Q., Kelly, C., Ruff, S. M., Zahedi, K., Shao, M., Bean, J., Mori, K., Barasch, J., & Devarajan, P. (2005). Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. The Lancet, 365(9466), 1231–1238.

    CAS  Google Scholar 

  52. Xu, A.,Wang, Y.,Renneberg, R.,Cautherley, G. W. H.,Chan, C. P. Y., & Lehmann, M. (2011). Lipocalin-2 as a prognostic and diagnostic marker for heart and stroke risks: Google patents.

  53. Khawaja, S., Jafri, L., Siddiqui, I., Hashmi, M., & Ghani, F. (2019). The utility of neutrophil gelatinase-associated Lipocalin (NGAL) as a marker of acute kidney injury (AKI) in critically ill patients. Biomarker Research, 7(1), 4.

    PubMed  PubMed Central  Google Scholar 

  54. Antonucci, E., Lippi, G., Ticinesi, A., Pigna, F., Guida, L., Morelli, I., Nouvenne, A., Borghi, L., & Meschi, T. (2014). Neutrophil gelatinase-associated lipocalin (NGAL): A promising biomarker for the early diagnosis of acute kidney injury (AKI). Acta Biomed, 85(3), 289–294.

    CAS  PubMed  Google Scholar 

  55. IV, W. F. P.,Maisel, A.,Kim, J., & Ronco, C. (2013). Neutrophil gelatinase associated lipocalin in acute kidney injury. Postgraduate Medicine, 125(6), 82–93.

  56. Mishra, J., Mori, K., Ma, Q., Kelly, C., Yang, J., Mitsnefes, M., Barasch, J., & Devarajan, P. (2004). Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. Journal of the American Society of Nephrology, 15(12), 3073–3082.

    PubMed  Google Scholar 

  57. Zhang, Y.-l.,Qiao, S.-k.,Wang, R.-y., & Guo, X.-n. (2018). NGAL attenuates renal ischemia/reperfusion injury through autophagy activation and apoptosis inhibition in rats. Chemico-Biological Interactions, 289, 40–46.

  58. Moretti, C., Cerrato, E., Cavallero, E., Lin, S., Rossi, M. L., Picchi, A., Sanguineti, F., Ugo, F., Palazzuoli, A., Bertaina, M., Presbitero, P., Shao-liang, C., Pozzi, R., Giammaria, M., Limbruno, U., Lefèvre, T., Gasparetto, V., Garbo, R., Omedè, P., Sheiban, I., Escaned, J., Biondi-Zoccai, G., Gaita, F., Perl, L., & D'Ascenzo, F. (2018). The EUROpean and Chinese cardiac and renal remote ischemic preconditioning study (EURO-CRIPS CardioGroup I): A randomized controlled trial. International Journal of Cardiology, 257, 1–6.

    PubMed  Google Scholar 

  59. Guo, S., Jian, L., Cheng, D., Pan, L., Liu, S., & Lu, C. (2019). Early renal-protective effects of remote ischemic preconditioning in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 25, 8602–8609.

    CAS  Google Scholar 

  60. Zhang, Y., Zhang, X., Chi, D., Wang, S., Wei, H., Yu, H., et al. (2016). Remote ischemic preconditioning for prevention of acute kidney injury in patients undergoing on-pump cardiac surgery: A systematic review and meta-analysis. Medicine, 95(37).

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Acknowledgments

This study was supported by National Institute for Medical Research Development (grant number: 97 7323).

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Correspondence to Mehryar Habibi Roudkenar.

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All experimental procedures were approved by research ethics committee of National Institute for Medical Research Development (IR. NIMAD. REC.1397.474).

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Alijani-Ghazyani, Z., Sabzevari, R., Roushandeh, A.M. et al. Transplantation of Umbilical Cord-Derived Mesenchymal Stem Cells Overexpressing Lipocalin 2 Ameliorates Ischemia-Induced Injury and Reduces Apoptotic Death in a Rat Acute Myocardial Infarction Model. Stem Cell Rev and Rep 16, 968–978 (2020). https://doi.org/10.1007/s12015-020-10007-8

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