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Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats

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Abstract

Cell-based therapies to restore heart function after infarction have been tested in pre-clinical models and clinical trials with mixed results, and will likely require both contractile cells and a vascular network to support them. We and others have shown that human endothelial colony forming cells (ECFC) combined with mesenchymal progenitor cells (MPC) can be used to “bio-engineer” functional human blood vessels. Here we investigated whether ECFC + MPC form functional vessels in ischemic myocardium and whether this affects cardiac function or remodeling. Myocardial ischemia/reperfusion injury (IRI) was induced in 12-week-old immunodeficient rats by ligation of the left anterior descending coronary artery. After 40 min, myocardium was reperfused and ECFC + MPC (2 × 106 cells, 2:3 ratio) or PBS was injected. Luciferase assays after injection of luciferase-labeled ECFC + MPC showed that 1,500 ECFC were present at day 14. Human ECFC-lined perfused vessels were directly visualized by femoral vein injection of a fluorescently-tagged human-specific lectin in hearts injected with ECFC + MPC but not PBS alone. While infarct size at day 1 was no different, LV dimensions and heart weight to tibia length ratios were lower in cell-treated hearts compared with PBS at 4 months, suggesting post-infarction remodeling was ameliorated by local cell injection. Fractional shortening, LV wall motion score, and fibrotic area were not different between groups at 4 months. However, pressure–volume loops demonstrated improved cardiac function and reduced volumes in cell-treated animals. These data suggest that myocardial delivery of ECFC + MPC at reperfusion may provide a therapeutic strategy to mitigate LV remodeling and cardiac dysfunction after IRI.

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References

  1. Roger VL, Go AS et al (2012) Executive summary: heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125(1):188–197

    Article  PubMed  Google Scholar 

  2. Cao F, Lin S et al (2006) In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation 113(7):1005–1014

    Article  PubMed  Google Scholar 

  3. Bifari F, Pacelli L, Krampera M (2010) Immunological properties of embryonic and adult stem cells. World J Stem Cells 2(3):50–60

    Article  PubMed  Google Scholar 

  4. Kamihata H, Matsubara H et al (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(9):1046–1052

    Article  PubMed  CAS  Google Scholar 

  5. Dohmann HF, Perin EC et al (2005) Transendocardial autologous bone marrow mononuclear cell injection in ischemic heart failure: postmortem anatomicopathologic and immunohistochemical findings. Circulation 112(4):521–526

    Article  PubMed  Google Scholar 

  6. Traverse JH, Henry TD et al (2012) Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA 308(22):2380–2389

    Article  PubMed  CAS  Google Scholar 

  7. Traverse JH, Henry TD 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. JAMA 306(19):2110–2119

    Article  PubMed  CAS  Google Scholar 

  8. Silva GV, Litovsky S et al (2005) Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 111(2):150–156

    Article  PubMed  CAS  Google Scholar 

  9. Wara AK, Croce K et al (2011) Bone marrow-derived CMPs and GMPs represent highly functional proangiogenic cells: implications for ischemic cardiovascular disease. Blood 118(24):6461–6464

    Article  PubMed  CAS  Google Scholar 

  10. Kawamoto A, Gwon HC et al (2001) Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 103(5):634–637

    Article  PubMed  CAS  Google Scholar 

  11. Yeh ET, Zhang S et al (2003) Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. Circulation 108(17):2070–2073

    Article  PubMed  Google Scholar 

  12. Losordo DW, Schatz RA et al (2007) Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation 115(25):3165–3172

    Article  PubMed  Google Scholar 

  13. Ii M, Horii M et al (2011) Synergistic effect of adipose-derived stem cell therapy and bone marrow progenitor recruitment in ischemic heart. Lab Invest 91(4):539–552

    Article  PubMed  CAS  Google Scholar 

  14. Katare R, Riu F et al (2011) Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132. Circ Res 109(8):894–906

    Article  PubMed  CAS  Google Scholar 

  15. Li TS, Cheng K et al (2012) Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol 59(10):942–953

    Article  PubMed  Google Scholar 

  16. Makkar RR, Smith RR et al (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379(9819):895–904

    Article  PubMed  Google Scholar 

  17. Bolli R, Chugh AR et al (2011) Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378(9806):1847–1857

    Article  PubMed  Google Scholar 

  18. Fadini GP, Losordo D, Dimmeler S (2012) Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res 110(4):624–637

    Article  PubMed  CAS  Google Scholar 

  19. Melero-Martin JM, De Obaldia ME et al (2008) Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circ Res 103(2):194–202

    Article  PubMed  CAS  Google Scholar 

  20. Foubert P, Matrone G et al (2008) Coadministration of endothelial and smooth muscle progenitor cells enhances the efficiency of proangiogenic cell-based therapy. Circ Res 103(7):751–760

    Article  PubMed  CAS  Google Scholar 

  21. Kang KT, Allen P, Bischoff J (2011) Bioengineered human vascular networks transplanted into secondary mice reconnect with the host vasculature and re-establish perfusion. Blood 118(25):6718–6721

    Article  PubMed  CAS  Google Scholar 

  22. Melero-Martin JM, Khan ZA et al (2007) In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. Blood 109(11):4761–4768

    Article  PubMed  CAS  Google Scholar 

  23. Allen P, Melero-Martin J, Bischoff J (2011) Type I collagen, fibrin and PuraMatrix matrices provide permissive environments for human endothelial and mesenchymal progenitor cells to form neovascular networks. J Tissue Eng Regen Med 5(4):e74–e86

    Article  PubMed  CAS  Google Scholar 

  24. Melero-Martin JM, Bischoff J (2008) Chapter 13. An in vivo experimental model for postnatal vasculogenesis. Methods Enzymol 445:303–329

    Article  PubMed  CAS  Google Scholar 

  25. Matsui T, Tao J et al (2001) Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 104(3):330–335

    Article  PubMed  CAS  Google Scholar 

  26. Wu JC, Cao F et al (2006) Proteomic analysis of reporter genes for molecular imaging of transplanted embryonic stem cells. Proteomics 6(23):6234–6249

    Article  PubMed  CAS  Google Scholar 

  27. Lang RM, Bierig M et al (2005) Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18(12):1440–1463

    Article  PubMed  Google Scholar 

  28. Das S, Aiba T et al (2012) Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. Circulation 126(18):2208–2219

    Article  PubMed  CAS  Google Scholar 

  29. Au P, Tam J, Fukumura D, Jain RK (2008) Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 111(9):4551–4558

    Article  PubMed  CAS  Google Scholar 

  30. Chen X, Aledia AS et al (2009) Prevascularization of a fibrin-based tissue construct accelerates the formation of functional anastomosis with host vasculature. Tissue Eng Part A 15(6):1363–1371

    Article  PubMed  CAS  Google Scholar 

  31. Chen X, Aledia AS et al (2010) Rapid anastomosis of endothelial progenitor cell-derived vessels with host vasculature is promoted by a high density of cotransplanted fibroblasts. Tissue Eng Part A 16(2):585–594

    Article  PubMed  CAS  Google Scholar 

  32. White SM, Hingorani R et al (2012) Longitudinal in vivo imaging to assess blood flow and oxygenation in implantable engineered tissues. Tissue Eng Part C Methods 18(9):697–709

    Article  PubMed  CAS  Google Scholar 

  33. Henry TD, Annex BH et al (2003) The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 107(10):1359–1365

    Article  PubMed  CAS  Google Scholar 

  34. Laham RJ, Chronos NA et al (2000) Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study. J Am Coll Cardiol 36(7):2132–2139

    Article  PubMed  CAS  Google Scholar 

  35. Lin YD, Luo CY et al (2012) Instructive nanofiber scaffolds with VEGF create a microenvironment for arteriogenesis and cardiac repair. Sci Transl Med 4(146):146ra109

    Google Scholar 

  36. Paul A, Chen G et al (2012) Genipin-crosslinked microencapsulated human adipose stem cells augment transplant retention resulting in attenuation of chronically infarcted rat heart fibrosis and cardiac dysfunction. Cell Transpl 21(12):2735–2751

    Google Scholar 

  37. Konoplyannikov M, Haider KH et al (2012) Activation of diverse signaling pathways by ex vivo delivery of multiple cytokines for myocardial repair. Stem Cells Dev 22(2):204–215

    Google Scholar 

  38. Kreutziger KL, Muskheli V et al (2011) Developing vasculature and stroma in engineered human myocardium. Tissue Eng Part A 17(9–10):1219–1228

    Article  PubMed  CAS  Google Scholar 

  39. Chong JJ (2012) Cell therapy for left ventricular dysfunction: an overview for cardiac clinicians. Heart Lung Circ 21(9):532–542

    Article  PubMed  Google Scholar 

  40. Vilahur G, Juan-Babot O et al (2011) Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction. J Mol Cell Cardiol 50(3):522–533

    Article  PubMed  CAS  Google Scholar 

  41. Carden DL, Granger DN (2000) Pathophysiology of ischaemia-reperfusion injury. J Pathol 190(3):255–266

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by HL09262 (JB, TR) and K08-HL098569 (MC). We thank Dr. David Zurokowski, Boston Children’s Hospital, for advice on the statistical analyses. We thank Thomas Neufeld for the excellent technical assistance on fibrosis analysis.

Conflict of interest

The authors have no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Vascular Biology Program and Department of Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA

    Kyu-Tae Kang & Joyce Bischoff

  2. College of Pharmacy, Duksung Women’s University, Seoul, Republic of Korea

    Kyu-Tae Kang

  3. Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Matthew Coggins, Chunyang Xiao & Anthony Rosenzweig

Authors
  1. Kyu-Tae Kang
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  2. Matthew Coggins
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  3. Chunyang Xiao
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  5. Joyce Bischoff
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Corresponding author

Correspondence to Joyce Bischoff.

Additional information

Kyu-Tae Kang and Matthew Coggins contributed equally to this study.

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Kang, KT., Coggins, M., Xiao, C. et al. Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats. Angiogenesis 16, 773–784 (2013). https://doi.org/10.1007/s10456-013-9354-9

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  • DOI: https://doi.org/10.1007/s10456-013-9354-9

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