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SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells

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Abstract

Stromal cell-derived factor 1-alpha (SDF) is a potent bone marrow chemokine capable of recruiting circulating progenitor populations to injured tissue. SDF has known angiogenic capabilities, but bone marrow-derived cellular contributions to tissue regeneration remain controversial. Bone marrow from DsRed-transgenic donors was transplanted into recipients to lineage-trace circulating cells after myocardial infarction (MI). SDF was delivered post-MI, and hearts were evaluated for recruitment and plasticity of bone marrow-derived populations. SDF treatment improved ventricular function, border zone vessel density, and CD31+ cell frequency post-MI. Bone marrow-derived endothelial cells were observed; these cells arose through both cell fusion and transdifferentiation. Circulating cells also adopted cardiomyocyte fates, but such events were exceedingly rare and almost exclusively resulted from cell fusion. SDF did not significantly alter the proportion of circulating cells that adopted non-hematopoietic fates. Mechanistic insight into the governance of circulating cells is essential to realizing the full potential of cytokine therapies.

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Abbreviations

MI:

Myocardial infarction

SDF:

Stromal cell-derived factor 1-alpha

References

  1. Beltrami, A. P., Barlucchi, L., Torella, D., Baker, M., Limana, F., Chimenti, S., et al. (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell, 114(6), 763–776.

    Article  PubMed  CAS  Google Scholar 

  2. Laugwitz, K.-L., Moretti, A., Lam, J., Gruber, P., Chen, Y., Woodard, S., et al. (2005). Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature, 433(7026), 647–653. https://doi.org/10.1038/nature03215.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Oh, H., Bradfute, S. B., Gallardo, T. D., Nakamura, T., Gaussin, V., Mishina, Y., et al. (2003). Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proceedings of the National Academy of Sciences of the United States of America, 100(21), 12313–12318. https://doi.org/10.1073/pnas.2132126100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Smart, N., Bollini, S., Dubé, K. N., Vieira, J. M., Zhou, B., Davidson, S., et al. (2011). De novo cardiomyocytes from within the activated adult heart after injury. Nature, 474(7353), 640–644. https://doi.org/10.1038/nature10188.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Macarthur, J. W., Cohen, J. E., McGarvey, J. R., Shudo, Y., Patel, J. B., Trubelja, A., et al. (2014). Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1α analog in a translational ovine myocardial infarction model. Circulation Research, 114(4), 650–659. https://doi.org/10.1161/CIRCRESAHA.114.302884.

    Article  PubMed  CAS  Google Scholar 

  6. Chung, E. S., Miller, L., Patel, A. N., Anderson, R. D., Mendelsohn, F. O., Traverse, J., et al. (2015). Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized phase II trial. European Heart Journal, 36(33), 2228–2238. https://doi.org/10.1093/eurheartj/ehv254.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Balsam, L. B., Wagers, A. J., Christensen, J. L., Kofidis, T., Weissman, I. L., & Robbins, R. C. (2004). Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature, 428(6983), 668–673. https://doi.org/10.1038/nature02460.

    Article  PubMed  CAS  Google Scholar 

  8. Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S. M., Li, B., et al. (2001). Bone marrow cells regenerate infarcted myocardium. Nature, 410(6829), 701–705. https://doi.org/10.1038/35070587.

    Article  PubMed  CAS  Google Scholar 

  9. Nygren, J. M., Jovinge, S., Breitbach, M., Säwén, P., Röll, W., Hescheler, J., et al. (2004). Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nature Medicine, 10(5), 494–501. https://doi.org/10.1038/nm1040.

    Article  PubMed  CAS  Google Scholar 

  10. Mouquet, F., Pfister, O., Jain, M., Oikonomopoulos, A., Ngoy, S., Summer, R., et al. (2005). Restoration of cardiac progenitor cells after myocardial infarction by self-proliferation and selective homing of bone marrow-derived stem cells. Circulation Research, 97(11), 1090–1092. https://doi.org/10.1161/01.RES.0000194330.66545.f5.

    Article  PubMed  CAS  Google Scholar 

  11. Wu, J. M. F., Hsueh, Y.-C., Ch’ang, H.-J., Luo, C.-Y., Wu, L.-W., Nakauchi, H., & Hsieh, P. C. H. (2015). Circulating cells contribute to cardiomyocyte regeneration after injury. Circulation Research, 116(4), 633–641. https://doi.org/10.1161/CIRCRESAHA.116.304564.

    Article  PubMed  CAS  Google Scholar 

  12. Wagers, A. J., Sherwood, R. I., Christensen, J. L., & Weissman, I. L. (2002). Little evidence for developmental plasticity of adult hematopoietic stem cells. Science, 297(5590), 2256–2259. https://doi.org/10.1126/science.1074807.

    Article  PubMed  CAS  Google Scholar 

  13. Jackson, K. A., Majka, S. M., Wang, H., Pocius, J., Hartley, C. J., Majesky, M. W., et al. (2001). Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. The Journal of Clinical Investigation, 107(11), 1395–1402. https://doi.org/10.1172/JCI12150.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. van Ramshorst, J., Bax, J. J., Beeres, S. L. M. A., Dibbets-Schneider, P., Roes, S. D., Stokkel, M. P. M., et al. (2009). Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. The Journal of the American Medical Association, 301(19), 1997–2004. https://doi.org/10.1001/jama.2009.685.

    Article  PubMed  Google Scholar 

  15. Traverse, J. H., Henry, T. D., Ellis, S. G., Pepine, C. J., Willerson, J. T., Zhao, D. X. M., et al. (2011). Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. The Journal of the American Medical Association, 306(19), 2110–2119. https://doi.org/10.1001/jama.2011.1670.

    Article  PubMed  CAS  Google Scholar 

  16. Strauer, B. E., Brehm, M., Zeus, T., Köstering, M., Hernandez, A., Sorg, R. V., et al. (2002). Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation, 106(15), 1913–1918. https://doi.org/10.1161/01.CIR.0000034046.87607.1C.

    Article  PubMed  Google Scholar 

  17. Schächinger, V., Erbs, S., Elsässer, A., Haberbosch, W., Hambrecht, R., Hölschermann, H., et al. (2006). Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. The New England Journal of Medicine, 355(12), 1210–1221. https://doi.org/10.1056/NEJMoa060186.

    Article  PubMed  Google Scholar 

  18. Tendera, M., Wojakowski, W., Ruzyłło, W., Chojnowska, L., Kepka, C., Tracz, W., et al. (2009). Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) trial. European Heart Journal, 30(11), 1313–1321. https://doi.org/10.1093/eurheartj/ehp073.

    Article  PubMed  Google Scholar 

  19. Bartunek, J., Vanderheyden, M., Vandekerckhove, B., Mansour, S., De Bruyne, B., De Bondt, P., et al. (2005). Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety. Circulation, 112(9 Suppl), I178–I183. https://doi.org/10.1161/CIRCULATIONAHA.104.522292.

    Article  PubMed  Google Scholar 

  20. Ascheim, D. D., Gelijns, A. C., Goldstein, D., Moye, L. A., Smedira, N., Lee, S., et al. (2014). Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary left ventricular assist devices. Circulation, 129(22), 2287–2296. https://doi.org/10.1161/CIRCULATIONAHA.113.007412.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Vintersten, K., Monetti, C., Gertsenstein, M., Zhang, P., Laszlo, L., Biechele, S., & Nagy, A. (2004). Mouse in red: red fluorescent protein expression in mouse ES cells, embryos, and adult animals. Genesis, 40(4), 241–246. https://doi.org/10.1002/gene.20095.

    Article  PubMed  CAS  Google Scholar 

  22. Hiesinger, W., Brukman, M. J., McCormick, R. C., Fitzpatrick, J. R., Frederick, J. R., Yang, E. C., et al. (2012). Myocardial tissue elastic properties determined by atomic force microscopy after stromal cell-derived factor 1α angiogenic therapy for acute myocardial infarction in a murine model. The Journal of Thoracic and Cardiovascular Surgery, 143(4), 962–966. https://doi.org/10.1016/j.jtcvs.2011.12.028.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Woo, Y. J., Grand, T. J., Berry, M. F., Atluri, P., Moise, M. A., Hsu, V. M., et al. (2005). Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy. The Journal of Thoracic and Cardiovascular Surgery, 130(2), 321–329. https://doi.org/10.1016/j.jtcvs.2004.11.041.

    Article  PubMed  CAS  Google Scholar 

  24. Czechowicz, A., Kraft, D., Weissman, I. L., & Bhattacharya, D. (2007). Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science, 318(5854), 1296–1299. https://doi.org/10.1126/science.1149726.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Saxena, A., Fish, J. E., White, M. D., Yu, S., Smyth, J. W. P., Shaw, R. M., et al. (2008). Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction. Circulation, 117(17), 2224–2231. https://doi.org/10.1161/CIRCULATIONAHA.107.694992.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Hiesinger, W., Perez-Aguilar, J. M., Atluri, P., Marotta, N. A., Frederick, J. R., Fitzpatrick, J. R., et al. (2011). Computational protein design to reengineer stromal cell-derived factor-1α generates an effective and translatable angiogenic polypeptide analog. Circulation, 124(11 Suppl), S18–S26. https://doi.org/10.1161/CIRCULATIONAHA.110.009431.

    Article  PubMed  PubMed Central  Google Scholar 

  27. MacArthur, J. W., Purcell, B. P., Shudo, Y., Cohen, J. E., Fairman, A., Trubelja, A., et al. (2013). Sustained release of engineered stromal cell-derived factor 1-α from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation, 128(11 Suppl 1), S79–S86. https://doi.org/10.1161/CIRCULATIONAHA.112.000343.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Murry, C. E., Soonpaa, M. H., Reinecke, H., Nakajima, H., Nakajima, H. O., Rubart, M., et al. (2004). Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature, 428(6983), 664–668. https://doi.org/10.1038/nature02446.

    Article  PubMed  CAS  Google Scholar 

  29. Asahara, T., Masuda, H., Takahashi, T., Kalka, C., Pastore, C., Silver, M., et al. (1999). Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circulation Research, 85(3), 221–228.

    Article  PubMed  CAS  Google Scholar 

  30. Huang, Y., Mao, Q., He, J., Su, J., Peng, Y., Liang, W., et al. (2017). Fusions of tumor-derived endothelial cells with dendritic cells induces antitumor immunity. Scientific Reports, 7, 46544. https://doi.org/10.1038/srep46544.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Fantin, A., Vieira, J. M., Gestri, G., Denti, L., Schwarz, Q., Prykhozhij, S., et al. (2010). Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood, 116(5), 829–840. https://doi.org/10.1182/blood-2009-12-257832.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Alvarez-Dolado, M., Pardal, R., Garcia-Verdugo, J. M., Fike, J. R., Lee, H. O., Pfeffer, K., et al. (2003). Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature, 425(6961), 968–973. https://doi.org/10.1038/nature02069.

    Article  PubMed  CAS  Google Scholar 

  33. Senyo, S. E., Steinhauser, M. L., Pizzimenti, C. L., Yang, V. K., Cai, L., Wang, M., et al. (2013). Mammalian heart renewal by pre-existing cardiomyocytes. Nature, 493(7432), 433–436. https://doi.org/10.1038/nature11682.

    Article  PubMed  CAS  Google Scholar 

  34. Kimura, W., Xiao, F., Canseco, D. C., Muralidhar, S., Thet, S., Zhang, H. M., et al. (2015). Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart. Nature, 523(7559), 226–230. https://doi.org/10.1038/nature14582.

    Article  PubMed  CAS  Google Scholar 

  35. Askari, A. T., Unzek, S., Popovic, Z. B., Goldman, C. K., Forudi, F., Kiedrowski, M., et al. (2003). Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. The Lancet, 362(9385), 697–703. https://doi.org/10.1016/S0140-6736(03)14232-8.

    Article  CAS  Google Scholar 

  36. Sundararaman, S., Miller, T. J., Pastore, J. M., Kiedrowski, M., Aras, R., & Penn, M. S. (2011). Plasmid-based transient human stromal cell-derived factor-1 gene transfer improves cardiac function in chronic heart failure. Gene Therapy, 18(9), 867–873. https://doi.org/10.1038/gt.2011.18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Ascione, R., Rowlinson, J., Avolio, E., Katare, R., Meloni, M., Spencer, H. L., et al. (2015). Migration towards SDF-1 selects angiogenin-expressing bone marrow monocytes endowed with cardiac reparative activity in patients with previous myocardial infarction. Stem Cell Research & Therapy, 6, 53. https://doi.org/10.1186/s13287-015-0028-y.

    Article  CAS  Google Scholar 

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Funding

This work was supported by the National Institutes of Health [R01 HL089315-01 to Y.J.W., S10OD010344-01A1 to Stanford Center for In Vivo Imaging] and the American Heart Association [14POST20380744 to A.B.G.]

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Author notes

  1. Andrew B. Goldstone and Cassandra E. Burnett contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiothoracic Surgery, School of Medicine, Stanford University, Stanford, CA, USA

    Andrew B. Goldstone, Jeffery E. Cohen, Michael J. Paulsen, Anahita Eskandari, Bryan E. Edwards, Arnar B. Ingason, Amanda N. Steele, Jay B. Patel, John W. MacArthur & Y. Joseph Woo

  2. Division of Blood and Marrow Transplantation, Department of Medicine, School of Medicine, Stanford University, Stanford, CA, USA

    Cassandra E. Burnett & Judith A. Shizuru

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  1. Andrew B. Goldstone
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Correspondence to Y. Joseph Woo.

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Human Subjects/Animal Subjects Statement

No human studies were carried out by the authors for this article. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

Conflict of Interest

Andrew B. Goldstone, MD, PhD; Jeffery E. Cohen, MD; and Y. Joseph Woo, MD are co-authors on the US patent application number 15/136,612. The remaining authors have no conflicts of interest.

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Associate Editor Joost Sluijter oversaw the review of this article

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Goldstone, A.B., Burnett, C.E., Cohen, J.E. et al. SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells. J. of Cardiovasc. Trans. Res. 11, 274–284 (2018). https://doi.org/10.1007/s12265-017-9772-y

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