Skip to main content

Advertisement

SpringerLink
Log in

Serial in vivo imaging of the porcine heart after percutaneous, intramyocardially injected 111In-labeled human mesenchymal stromal cells

  • Original Paper
  • Published:
The International Journal of Cardiovascular Imaging Aims and scope Submit manuscript

Abstract

This pilot trial aimed to investigate the utilization of 111In-labeling of mesenchymal stromal cells (MSC) for in vivo tracking after intramyocardial transplantation in a xenotransplantation model with gender mismatched cells. Human male MSC were expanded ex vivo and labeled with 111In-tropolone. Ten female pigs were included. The labeled cells were transplanted intramyocardially using a percutaneous injection system. The 111In activity was determined using gamma camera imaging. Excised hearts were analyzed by fluorescence in situ hybridization (FISH) and microscopy. Gamma camera imaging revealed focal cardiac 111In accumulations up to 6 days after injection (N = 4). No MSC could be identified with FISH, and microscopy identified widespread acute inflammation. Focal 111In accumulation, inflammation but no human MSC were similarly seen in pigs (N = 2) after immunosuppression. A comparable retention of 111In activity was observed after intramyocardial injection of 111In-tropolone (without cells) (N = 2), but without sign of myocardial inflammation. Injection of labeled non-viable cells (N = 1) also led to high focal 111In activity up to 6 days after intramyocardial injection. As a positive control of the FISH method, we identified labeled cells both in culture and immediately after cell injection in one pig. This pilot trial suggests that after intramyocardial injection 111In stays in the myocardium despite possible disappearance of labeled cells. This questions the clinical use of 111In-labeled cells for tracking. The results further suggest that xenografting of human MSC into porcine hearts leads to inflammation contradicting previous studies implying a special immunoprivileged status for MSC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Ripa RS, Jørgensen E, Wang Y, Thune JJ, Nilsson JC, Søndergaard L, Johnsen HE, Køber L, Grande P, Kastrup J (2006) Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 113:1983–1992

    Article  CAS  PubMed  Google Scholar 

  2. Schächinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221

    Article  PubMed  Google Scholar 

  3. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K (2006) Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 355:1199–1209

    Article  CAS  PubMed  Google Scholar 

  4. Beeres SL, Bengel FM, Bartunek J, Atsma DE, Hill JM, Vanderheyden M, Penicka M, Schalij MJ, Wijns W, Bax JJ (2007) Role of imaging in cardiac stem cell therapy. J Am Coll Cardiol 49:1137–1148

    Article  PubMed  Google Scholar 

  5. 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  CAS  PubMed  Google Scholar 

  6. Haack-Sorensen M, Friis T, Bindslev L, Mortensen S, Johnsen HE, Kastrup J (2008) Comparison of different culture conditions for human mesenchymal stromal cells for clinical stem cell therapy. Scand J Clin Lab Invest 68:192–203

    Article  CAS  PubMed  Google Scholar 

  7. Haack-Sorensen M, Friis T, Kastrup J (2008) Mesenchymal stromal cell and mononuclear cell therapy in heart disease. Future Cardiology 4:481–494

    Article  PubMed  Google Scholar 

  8. Bindslev L, Haack-Sørensen M, Bisgaard K, Kragh L, Mortensen S, Hesse B, Kjaer A, Kastrup J (2006) Labelling of human mesenchymal stem cells with indium-111 for SPECT imaging: effect on cell proliferation and differentiation. Eur J Nucl Med Mol Imaging 33:1171–1177

    Article  CAS  PubMed  Google Scholar 

  9. Kastrup J, Jørgensen E, Ruck A, Tägil K, Glogar D, Ruzyllo W, Bøtker HE, Dudek D, Drvota V, Hesse B, Thuesen L, Blomberg P, Gyöngyösi M, Sylvén C (2005) Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris a randomized double-blind placebo-controlled study: the Euroinject One trial. J Am Coll Cardiol 45:982–988

    Article  CAS  PubMed  Google Scholar 

  10. Haack-Sorensen M, Bindslev L, Mortensen S, Friis T, Kastrup J (2007) The influence of freezing and storage on the characteristics and functions of human mesenchymal stromal cells isolated for clinical use. Cytotherapy 9:328–337

    Article  CAS  PubMed  Google Scholar 

  11. Aicher A, Brenner W, Zuhayra M, Badorff C, Massoudi S, Assmus B, Eckey T, Henze E, Zeiher AM, Dimmeler S (2003) Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 107:2134–2139

    Article  PubMed  Google Scholar 

  12. Brenner W, Aicher A, Eckey T, Massoudi S, Zuhayra M, Koehl U, Heeschen C, Kampen WU, Zeiher AM, Dimmeler S, Henze E (2004) 111In-labeled CD34+ hematopoietic progenitor cells in a rat myocardial infarction model. J Nucl Med 45:512–518

    CAS  PubMed  Google Scholar 

  13. Jin Y, Kong H, Stodilka RZ, Wells RG, Zabel P, Merrifield PA, Sykes J, Prato FS (2005) Determining the minimum number of detectable cardiac-transplanted 111In-tropolone-labelled bone-marrow-derived mesenchymal stem cells by SPECT. Phys Med Biol 50:4445–4455

    Article  PubMed  Google Scholar 

  14. Gholamrezanezhad A, Mirpour S, Ardekani JM, Bagheri M, Alimoghadam K, Yarmand S, Malekzadeh R (2009) Cytotoxicity of 111In-oxine on mesenchymal stem cells: a time-dependent adverse effect. Nucl Med Commun 30:210–216

    Article  CAS  PubMed  Google Scholar 

  15. Thakur ML, Segal AW, Louis L, Welch MJ, Hopkins J, Peters TJ (1977) Indium-111-labeled cellular blood components: mechanism of labeling and intracellular location in human neutrophils. J Nucl Med 18:1022–1026

    CAS  PubMed  Google Scholar 

  16. Hou D, Youssef EA, Brinton TJ, Zhang P, Rogers P, Price ET, Yeung AC, Johnstone BH, Yock PG, March KL (2005) Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 112:I150–I156

    PubMed  Google Scholar 

  17. Schächinger V, Aicher A, Dobert N, Rover R, Diener J, Fichtlscherer S, Assmus B, Seeger FH, Menzel C, Brenner W, Dimmeler S, Zeiher AM (2008) Pilot trial on determinants of progenitor cell recruitment to the infarcted human myocardium. Circulation 118:1425–1432

    Article  PubMed  Google Scholar 

  18. Tossios P, Krausgrill B, Schmidt M, Fischer T, Halbach M, Fries JW, Fahnenstich S, Frommolt P, Heppelmann I, Schmidt A, Schomacker K, Fischer JH, Bloch W, Mehlhorn U, Schwinger RH, Muller-Ehmsen J (2008) Role of balloon occlusion for mononuclear bone marrow cell deposition after intracoronary injection in pigs with reperfused myocardial infarction. Eur Heart J 29:1911–1921

    Article  CAS  PubMed  Google Scholar 

  19. Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, Muul L, Hofmann T (2002) Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci USA 99:8932–8937

    Article  CAS  PubMed  Google Scholar 

  20. Amado LC, Saliaris AP, Schuleri KH, St JM, 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  CAS  PubMed  Google Scholar 

  21. 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  CAS  PubMed  Google Scholar 

  22. Liechty KW, MacKenzie TC, Shaaban AF, Radu A, Moseley AM, Deans R, Marshak DR, Flake AW (2000) Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 6:1282–1286

    Article  CAS  PubMed  Google Scholar 

  23. Allers C, Sierralta WD, Neubauer S, Rivera F, Minguell JJ, Conget PA (2004) Dynamic of distribution of human bone marrow-derived mesenchymal stem cells after transplantation into adult unconditioned mice. Transplantation 78:503–508

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  25. Plotnikov AN, Shlapakova I, Szabolcs MJ, Danilo P Jr, Lorell BH, Potapova IA, Lu Z, Rosen AB, Mathias RT, Brink PR, Robinson RB, Cohen IS, Rosen MR (2007) Xenografted adult human mesenchymal stem cells provide a platform for sustained biological pacemaker function in canine heart. Circulation 116:706–713

    Article  PubMed  Google Scholar 

  26. Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE (2006) Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 108:2114–2120

    Article  CAS  PubMed  Google Scholar 

  27. Poncelet AJ, Vercruysse J, Saliez A, Gianello P (2007) Although pig allogeneic mesenchymal stem cells are not immunogenic in vitro, intracardiac injection elicits an immune response in vivo. Transplantation 83:783–790

    Article  PubMed  Google Scholar 

  28. Grinnemo KH, Mansson-Broberg A, Leblanc K, Corbascio M, Wardell E, Siddiqui AJ, Hao X, Sylven C, Dellgren G (2006) Human mesenchymal stem cells do not differentiate into cardiomyocytes in a cardiac ischemic xenomodel. Ann Med 38:144–153

    Article  CAS  PubMed  Google Scholar 

  29. Goussetis E, Manginas A, Koutelou M, Peristeri I, Theodosaki M, Kollaros N, Leontiadis E, Theodorakos A, Paterakis G, Karatasakis G, Cokkinos DV, Graphakos S (2006) Intracoronary infusion of CD133+ and CD133-CD34+ selected autologous bone marrow progenitor cells in patients with chronic ischemic cardiomyopathy: cell isolation, adherence to the infarcted area, and body distribution. Stem Cells 24:2279–2283

    Article  CAS  PubMed  Google Scholar 

  30. Caveliers V, De Keulenaer G, Everaert H, Van Riet I, Van Camp G, Verheye S, Roland J, Schoors D, Franken PR, Schots R (2007) In vivo visualization of 111In labeled CD133+ peripheral blood stem cells after intracoronary administration in patients with chronic ischemic heart disease. Q J Nucl Med Mol Imaging 51:61–66

    CAS  PubMed  Google Scholar 

  31. Kurpisz M, Czepczynski R, Grygielska B, Majewski M, Fiszer D, Jerzykowska O, Sowinski J, Siminiak T (2007) Bone marrow stem cell imaging after intracoronary administration. Int J Cardiol 121:194–195

    Article  CAS  PubMed  Google Scholar 

  32. Amsalem Y, Mardor Y, Feinberg MS, Landa N, Miller L, Daniels D, Ocherashvilli A, Holbova R, Yosef O, Barbash IM, Leor J (2007) Iron-oxide labeling and outcome of transplanted mesenchymal stem cells in the infarcted myocardium. Circulation 116:I38–I45

    Article  CAS  PubMed  Google Scholar 

  33. Terrovitis J, Stuber M, Youssef A, Preece S, Leppo M, Kizana E, Schar M, Gerstenblith G, Weiss RG, Marban E, Abraham MR (2008) Magnetic resonance imaging overestimates ferumoxide-labeled stem cell survival after transplantation in the heart. Circulation 117:1555–1562

    Article  PubMed  Google Scholar 

  34. Gyongyosi M, Blanco J, Marian T, Tron L, Petnehazy O, Petrasi Z, Hemetsberger R, Rodriguez J, Font G, Pavo IJ, Kertesz I, Balkay L, Pavo N, Posa A, Emri M, Galuska L, Kraitchman DL, Wojta J, Huber K, Glogar D (2008) Serial Noninvasive In Vivo Positron Emission Tomographic Tracking of Percutaneously Intramyocardially Injected Autologous Porcine Mesenchymal Stem Cells Modified for Transgene Reporter Gene Expression. Circ Cardiovasc Imaging 1:94–103

    Article  PubMed  Google Scholar 

  35. Zhou R, Thomas DH, Qiao H, Bal HS, Choi SR, Alavi A, Ferrari VA, Kung HF, Acton PD (2005) In vivo detection of stem cells grafted in infarcted rat myocardium. J Nucl Med 46:816–822

    CAS  PubMed  Google Scholar 

Download references

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Cardiology, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Stig Lyngbæk, Rasmus S. Ripa, Erik Jørgensen & Jens Kastrup

  2. Cardiac Stem Cell Laboratory, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Stig Lyngbæk, Mandana Haack-Sørensen & Jens Kastrup

  3. Department of Clinical Physiology, Nuclear Medicine and PET & Cluster for Molecular Imaging, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Annette Cortsen, Linda Kragh, Andreas Kjær & Birger Hesse

  4. Department of Pathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Claus B. Andersen

  5. Department of Clinical Physiology and Nuclear Medicine, Frederiksberg Hospital, Nordre Fasanvej 57, 2000, Frederiksberg, Denmark

    Rasmus S. Ripa

Authors
  1. Stig Lyngbæk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rasmus S. Ripa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mandana Haack-Sørensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Annette Cortsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Linda Kragh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claus B. Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Erik Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andreas Kjær
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jens Kastrup
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Birger Hesse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rasmus S. Ripa.

Additional information

Stig Lyngbaek and Rasmus S. Ripa contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lyngbæk, S., Ripa, R.S., Haack-Sørensen, M. et al. Serial in vivo imaging of the porcine heart after percutaneous, intramyocardially injected 111In-labeled human mesenchymal stromal cells. Int J Cardiovasc Imaging 26, 273–284 (2010). https://doi.org/10.1007/s10554-009-9532-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10554-009-9532-4

Keywords

Search

Navigation