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Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction

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Abstract

Transplantation of stem cells may improve regional perfusion and post-infarct ventricular function, but the optimal dose and efficacy of cell delivery via the intravenous route has not been determined. This study tested the hypothesis that intravenous infusion of bone marrow-derived mesenchymal stem cells (MSCs) enhances regional perfusion and improves ventricular function after myocardial infarction. In a closed-chest pig model, the LAD coronary artery was occluded for 75 min by angioplasty balloon inflation followed by 12 weeks of reperfusion. After 15 min of reperfusion, pigs randomly received 1 of 4 treatments: (1) Vehicle (Control, n = 10); (2) 1 × 106 MSCs/kg (1 mill, n = 7); (3) 3 × 106 MSCs/kg (3 mill, n = 8) and (4) 10 × 106 MSCs/kg (10 mill, n = 8). Angiogenesis was demonstrated by immunohistochemical staining, myocardial blood flow (steady state and vasodilator reserve) was measured using 15 µm neutron-activated microspheres, and cardiac function was determined by contrast left ventriculography (ejection fraction) and pressure–volume relationships. After 12 week of reperfusion, von Willebrand Factor-positive vessels and tissue vascular endothelial growth factor (VEGF) expression in the scar zone was significantly greater in all MSCs-treated animals relative to Control. Steady state myocardial blood flow in the scar tissue was comparable among groups. However, adenosine recruited vasodilator reserve in the scar zone induced by intracoronary adenosine was significantly higher in the MSC-treated animals compared to Control. Furthermore, preload-recruitable stroke work and systolic performance were significantly greater compared to Control. In conclusion, these data demonstrate that intravenous delivery of MSCs during early reperfusion augments vasculogenesis, enhances regional perfusion, and improves post-infarct ventricular function. The results suggest that intravenous infusion of MSCs is an effective modality for the treatment of ischemia/reperfusion induced myocardial injury.

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References

  1. Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM (2005) Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci USA 102:11474–11479

    Article  PubMed  CAS  Google Scholar 

  2. Amado LC, Schuleri KH, Saliaris AP, Boyle AJ, Helm R, Oskouei B, Centola M, Eneboe V, Young R, Lima JA, Lardo AC, Heldman AW, Hare JM (2006) Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy. J Am Coll Cardiol 48:2116–2124

    Article  PubMed  Google Scholar 

  3. Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS (2003) Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 362:697–703

    Article  PubMed  CAS  Google Scholar 

  4. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM (2002) Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 106:3009–3017

    Article  PubMed  Google Scholar 

  5. Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428:668–673

    Article  PubMed  CAS  Google Scholar 

  6. Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH, Kloner RA, Leor J (2003) Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation 108:863–868

    Article  PubMed  Google Scholar 

  7. Caparrelli DJ, Cattaneo SM, Shake JG, Flynn EC, Meyers J, Baumgartner WA, Martin BJ (2001) Cellular myoplasty with mesenchymal stem cells results in improved cardiac performance in a swine model of myocardial infarction. Circulation 104:II-599

    Google Scholar 

  8. Consigny PM, Verrier ED, Payne BD, Edelist G, Jester J, Baer RW, Vlahakes GJ, Hoffman JI (1982) Acute and chronic microsphere loss from canine left ventricular myocardium. Am J Physiol 242:H392–H404

    PubMed  CAS  Google Scholar 

  9. Davani S, Marandin A, Mersin N, Royer B, Kantelip B, Herve P, Etievent JP, Kantelip JP (2003) Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a rat cellular cardiomyoplasty model. Circulation 108:II-253–II-258

    Article  Google Scholar 

  10. De Jonge MK, van den Bos GC, Elzinga G (1980) Changes of microsphere density with time in myocardial infarcts in dogs. Cardiovasc Res 14:741–744

    Article  PubMed  Google Scholar 

  11. Dodge HT, Sandler H, Ballew DW (1960) The use of bigplane angiography for the measurement of left ventricular volume in man. Eur Heart J 60:762–776

    CAS  Google Scholar 

  12. Fischer P, Hilfiker-Kleiner D (2007) Survival pathways in hypertrophy and heart failure: the gp130-STAT axis. Basic Res Cardiol 102:393–411

    Article  PubMed  CAS  Google Scholar 

  13. Fuchs S, Baffour R, Zhou YF, Shou M, Pierre A, Tio FO, Weissman NJ, Leon MB, Epstein SE, Kornowski R (2001) Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol 37:1726–1732

    Article  PubMed  CAS  Google Scholar 

  14. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 11:367–368

    Article  PubMed  CAS  Google Scholar 

  15. Grogaard HK, Sigurjonsson OE, Brekke M, Klow NE, Landsverk KS, Lyberg T, Eriksen M, Egeland T, Ilebekk A (2007) Cardiac accumulation of bone marrow mononuclear progenitor cells after intracoronary or intravenous injection in pigs subjected to acute myocardial infarction with subsequent reperfusion. Cardiovasc Revasc Med 8:21–27

    Article  PubMed  Google Scholar 

  16. Hiasa K, Egashira K, Kitamoto S, Ishibashi M, Inoue S, Ni W, Zhao Q, Nagata S, Katoh M, Sata M, Takeshita A (2004) Bone marrow mononuclear cell therapy limits myocardial infarct size through vascular endothelial growth factor. Basic Res Cardiol 99:165–172

    Article  PubMed  CAS  Google Scholar 

  17. Hudspeth DA, Nakanishi K, Vinten-Johansen J, Zhao ZQ, McGee DS, Williams MW, Hammon JW Jr (1994) Adenosine in blood cardioplegia prevents postischemic dysfunction in ischemically injured hearts. Ann Thorac Surg 58:1637–1644

    Article  PubMed  CAS  Google Scholar 

  18. Jugdutt BI, Hutchins GM, Bulkley BH, Becker LC (1979) The loss of radioactive microspheres from canine necrotic myocardium. Circ Res 45:746–756

    PubMed  CAS  Google Scholar 

  19. Katz AM (1995) Cell death in the failing heart: role of an unnatural growth response to overload. Clin Cardiol 18(Suppl IV):IV-36–IV-44

    CAS  Google Scholar 

  20. Kern MJ (2000) Coronary physiology revisited: practical insights from the cardiac catheterization laboratory. Circulation 101:1344–1351

    PubMed  CAS  Google Scholar 

  21. Kloner RA, Ganote CE, Jennings RB (1974) The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 54:1496–1508

    Article  PubMed  CAS  Google Scholar 

  22. Koch KC, Schaefer WM, Liehn EA, Rammos C, Mueller D, Schroeder J, Dimassi T, Stopinski T, Weber C (2006) Effect of catheter-based transendocardial delivery of stromal cell-derived factor 1alpha on left ventricular function and perfusion in a porcine model of myocardial infarction. Basic Res Cardiol 101:69–77

    Article  PubMed  CAS  Google Scholar 

  23. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S (2001) Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436

    Article  PubMed  CAS  Google Scholar 

  24. Kono A, Maughan WL, Sunagawa K, Hamilton K, Sagawa K, Weisfeldt ML (1984) The use of left ventricular end-ejection pressure and peak pressure in the estimation of the end-systolic pressure–volume relationship. Circulation 70:1057–1065

    PubMed  CAS  Google Scholar 

  25. Krause U, Harter C, Seckinger A, Wolf D, Reinhard A, Bea F, Dengler T, Hardt S, Ho A, Katus HA, Kuecherer H, Hansen A (2007) Intravenous delivery of autologous mesenchymal stem cells limits infarct size and improves left ventricular function in the infarcted porcine heart. Stem Cells Dev 16:31–37

    Article  PubMed  CAS  Google Scholar 

  26. Kudo M, Wang Y, Wani MA, Xu M, Ayub A, Ashraf M (2003) Implantation of bone marrow stem cells reduces the infarction and fibrosis in ischemic mouse heart. J Mol Cell Cardiol 35:1113–1119

    Article  PubMed  CAS  Google Scholar 

  27. Kuethe F, Figulla HR, Voth M, Richartz BM, Opfermann T, Sayer HG, Krack A, Fritzenwanger M, Hoffken K, Gottschild D, Werner GS (2004) [Mobilization of stem cells by granulocyte colony-stimulating factor for the regeneration of myocardial tissue after myocardial infarction]. Dtsch Med Wochenschr 129:424–428

    PubMed  CAS  Google Scholar 

  28. Little WC, Cheng C-P, Mumma M, Igarashi Y, Vinten-Johansen J, Johnston WE (1989) Comparison of measures of left ventricular contractile performance derived from pressure-volume loops in conscious dogs. Circulation 80:1378–1387

    PubMed  CAS  Google Scholar 

  29. Lyngbaek S, Schneider M, Hansen JL, Sheikh SP (2007) Cardiac regeneration by resident stem and progenitor cells in the adult heart. Basic Res Cardiol 102:101–114

    Article  PubMed  Google Scholar 

  30. Matsubara H, Nishiura T, Fujiyama S, Tsutsumi Y, Ozono R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Murohara T, Imaizumi T, Iwasaka T (2001) Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 104:1046–1052

    Article  PubMed  Google Scholar 

  31. Murdock RH Jr, Cobb FR (1980) Effects of infarcted myocardium on regional blood flow measurements to ischemic regions in canine heart. Circ Res 47:701–709

    PubMed  Google Scholar 

  32. Murtagh B, Higano S, Lennon R, Mathew V, Holmes DR Jr, Lerman A (2003) Role of incremental doses of intracoronary adenosine for fractional flow reserve assessment. Am Heart J 146:99–105

    Article  PubMed  CAS  Google Scholar 

  33. Mykytenko J, Kerendi F, Reeves JG, Kin H, Zatta AJ, Jiang R, Guyton RA, Vinten-Johansen J, Zhao ZQ (2007) Long-term inhibition of myocardial infarction by postconditioning during reperfusion. Basic Res Cardiol 102:90–100

    Article  PubMed  CAS  Google Scholar 

  34. Orlic D, Hill JM, Arai AE (2002) Stem cells for myocardial regeneration. Circ Res 91:1092–1102

    Article  PubMed  CAS  Google Scholar 

  35. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. PNAS 98:10344–10349

    Article  PubMed  CAS  Google Scholar 

  36. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    Article  PubMed  CAS  Google Scholar 

  37. Price MJ, Chou CC, Frantzen M, Miyamoto T, Kar S, Lee S, Shah PK, Martin BJ, Lill M, Forrester JS, Chen PS, Makkar RR (2006) Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties. Int J Cardiol 111:231–239

    Article  PubMed  Google Scholar 

  38. Saito T, Kuang J-Q, Bittira B, Al-Khaldi A, Chiu RC (2002) Xenotrasplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg 74:19–24

    Article  PubMed  Google Scholar 

  39. Schuh A, Liehn EA, Sasse A, Hristov M, Sobota R, Kelm M, Merx MW, Weber C (2008) Transplantation of endothelial progenitor cells improves neovascularization and left ventricular function after myocardial infarction in a rat model. Basic Res Cardiol 103:69–77

    Article  PubMed  Google Scholar 

  40. Sonnenblick EH, Anversa P (1999) Models and remodeling: mechanisms and clinical implications. Cardiologia 44:609–617

    PubMed  CAS  Google Scholar 

  41. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106:1913–1918

    Article  PubMed  Google Scholar 

  42. Tang YL, Zhao Q, Zhang YC, Cheng L, Liu M, Shi J, Yang YZ, Pan C, Ge J, Phillips MI (2004) Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept 117:3–10

    Article  PubMed  CAS  Google Scholar 

  43. Templin C, Kotlarz D, Marquart F, Faulhaber J, Brendecke V, Schaefer A, Tsikas D, Bonda T, Hilfiker-Kleiner D, Ohl L, Naim HY, Foerster R, Drexler H, Limbourg FP (2006) Transcoronary delivery of bone marrow cells to the infarcted murine myocardium: feasibility, cellular kinetics, and improvement in cardiac function. Basic Res Cardiol 101:301–310

    Article  PubMed  Google Scholar 

  44. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105:93–98

    Article  PubMed  Google Scholar 

  45. Tomita S, Li R-K, Weisel RD, Mickle DAG, Kim E-J, Sakai T, Jia Z-Q (1999) Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 100(suppl II):II-247–II-256

    CAS  Google Scholar 

  46. Tse H-F, Kwong Y-L, Chan JKF, Lo G, Ho C-L, Lau C-P (2003) Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 361:47–49

    Article  PubMed  Google Scholar 

  47. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75:389–397

    Article  PubMed  CAS  Google Scholar 

  48. Vandervelde S, van Luyn MJ, Tio RA, Harmsen MC (2005) Signaling factors in stem cell-mediated repair of infarcted myocardium. J Mol Cell Cardiol 39:363–376

    Article  PubMed  CAS  Google Scholar 

  49. Zhao Z-Q, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Laurie Berley Injave, and Sara Katzmark for their technical support and assistance in the preparation of this manuscript. This study was funded in part by Osiris Therapeutics, Inc., NIH grants HL64886 (Z.-Q. Zhao) and HL69487 (J. Vinten-Johansen), as well as funds from the Carlyle Fraser Heart Center of Emory Crawford Long Hospital.

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Authors and Affiliations

  1. Cardiothoracic Research Laboratory, Division of Cardiothoracic Surgery, Emory Crawford Long Hospital, 550 Peachtree Street, NE, Atlanta, GA, 30308, USA

    Michael E. Halkos, Zhi-Qing Zhao, Faraz Kerendi, Ning-Ping Wang, Rong Jiang, L. Susan Schmarkey, Hajime Kin, Robert A. Guyton & Jakob Vinten-Johansen PhD

  2. Osiris Therapeutics, Baltimore, MD, USA

    Bradley J. Martin

  3. Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA

    Arshed A. Quyyumi & Walter L. Few

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  1. Michael E. Halkos
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  2. Zhi-Qing Zhao
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  3. Faraz Kerendi
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  4. Ning-Ping Wang
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  5. Rong Jiang
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  6. L. Susan Schmarkey
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  8. Arshed A. Quyyumi
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  10. Hajime Kin
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  11. Robert A. Guyton
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  12. Jakob Vinten-Johansen PhD
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Correspondence to Jakob Vinten-Johansen PhD.

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Returned for 1. Revision: 11 April 2008 1. Revision received: 30 May 2008 Returned for 2. Revision: 11 June 2008 2. Revision received: 7 July 2008 Returned for 3. Revision: 9 July 2008 3. Revision received: 14 July 2008

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Halkos, M.E., Zhao, ZQ., Kerendi, F. et al. Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction. Basic Res Cardiol 103, 525–536 (2008). https://doi.org/10.1007/s00395-008-0741-0

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