Molecular Imaging and Biology

, Volume 11, Issue 3, pp 178–187 | Cite as

Comparison of Optical Bioluminescence Reporter Gene and Superparamagnetic Iron Oxide MR Contrast Agent as Cell Markers for Noninvasive Imaging of Cardiac Cell Transplantation

  • Ian Y. Chen
  • Joan M. Greve
  • Olivier Gheysens
  • Jürgen K. Willmann
  • Martin Rodriguez-Porcel
  • Pauline Chu
  • Ahmad Y. Sheikh
  • Anthony Z. Faranesh
  • Ramasamy Paulmurugan
  • Phillip C. Yang
  • Joseph C. Wu
  • Sanjiv S. Gambhir
Research Article

Abstract

Purpose

In this study, we compared firefly luciferase (Fluc) reporter gene and superparamagnetic iron oxide (Feridex) as cell markers for longitudinal monitoring of cardiomyoblast graft survival using optical bioluminescence imaging (BLI) and magnetic resonance imaging (MRI), respectively.

Procedures

Rats (n = 31) underwent an intramyocardial injection of cardiomyoblasts (2 × 106) labeled with Fluc, Feridex, or no marker (control) or an injection of Feridex alone (75 μg). Afterward, rats were serially imaged with BLI or MRI and killed at different time points for histological analysis.

Results

BLI revealed a drastically different cell survival kinetics (half-life = 2.65 days over 6 days) than that revealed by MRI (half-life = 16.8 days over 80 days). Injection of Feridex alone led to prolonged tissue retention of Feridex (≥16 days) and persistent MR signal (≥42 days).

Conclusions

Fluc BLI reporter gene imaging is a more accurate gauge of transplanted cell survival as compared to MRI of Feridex-labeled cells.

Key words

Optical bioluminescence imaging Magnetic resonance imaging Reporter gene Contrast agent Cell marker Cell transplantation 

Notes

Acknowledgments

This work was supported in part by NHLBI 5R01HL078632 (S.S.G.), NCI ICMIC P50 CA114747 (S.S.G.), NCI SAIRP (S.S.G.), American Heart Association Pre-doctoral Fellowship (I.Y.C.), Stanford Bio-X Graduate Student Fellowship (I.Y.C), Swiss Foundation of Medical-Biological Grants (JKW), Novartis Research Foundation (JKW), Swiss Society of Radiology (JKW), and AHA Beginning Grant in Aid (J.C.W.).

References

  1. 1.
    Reffelmann T, Kloner RA (2003) Cellular cardiomyoplasty–cardiomyocytes, skeletal myoblasts, or stem cells for regenerating myocardium and treatment of heart failure? Cardiovasc Res 58:358–368PubMedCrossRefGoogle Scholar
  2. 2.
    Rosenzweig A (2006) Cardiac cell therapy—mixed results from mixed cells. N Engl J Med 355:1274–1277PubMedCrossRefGoogle Scholar
  3. 3.
    Janssens S et al (2006) Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367:113–121PubMedCrossRefGoogle Scholar
  4. 4.
    Frangioni JV, Hajjar RJ (2004) In vivo tracking of stem cells for clinical trials in cardiovascular disease. Circulation 110:3378–3383PubMedCrossRefGoogle Scholar
  5. 5.
    Bengel FM, Schachinger V, Dimmeler S (2005) Cell-based therapies and imaging in cardiology. Eur J Nucl Med Mol Imaging 32(Suppl 2):S404–S416PubMedCrossRefGoogle Scholar
  6. 6.
    Zhou R, Acton PD, Ferrari VA (2006) Imaging stem cells implanted in infarcted myocardium. J Am Coll Cardiol 48:2094–2106PubMedCrossRefGoogle Scholar
  7. 7.
    Wu JC et al (2003) Molecular imaging of cardiac cell transplantation in living animals using optical bioluminescence and positron emission tomography. Circulation 108:1302–1305PubMedCrossRefGoogle Scholar
  8. 8.
    Zhou R et al (2005) In vivo detection of stem cells grafted in infarcted rat myocardium. J Nucl Med 46:816–822PubMedGoogle Scholar
  9. 9.
    Kraitchman DL et al (2003) In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 107:2290–2293PubMedCrossRefGoogle Scholar
  10. 10.
    Genove G, DeMarco U, Xu H, Goins WF, Ahrens ET (2005) A new transgene reporter for in vivo magnetic resonance imaging. Nat Med 11:450–454PubMedCrossRefGoogle Scholar
  11. 11.
    Hofmann M et al (2005) Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 111:2198–2202PubMedCrossRefGoogle Scholar
  12. 12.
    Ray P et al (2001) Monitoring gene therapy with reporter gene imaging. Semin Nucl Med 31:312–320PubMedCrossRefGoogle Scholar
  13. 13.
    Chen IY et al (2004) Micro-positron emission tomography imaging of cardiac gene expression in rats using bicistronic adenoviral vector-mediated gene delivery. Circulation 109:1415–1420PubMedCrossRefGoogle Scholar
  14. 14.
    Gheysens O et al (2006) Noninvasive evaluation of immunosuppressive drug efficacy on acute donor cell survival. Mol Imaging Biol 8:163–170PubMedCrossRefGoogle Scholar
  15. 15.
    Matuszewski L et al (2005) Cell tagging with clinically approved iron oxides: feasibility and effect of lipofection, particle size, and surface coating on labeling efficiency. Radiology 235:155–161PubMedCrossRefGoogle Scholar
  16. 16.
    Arbab AS et al (2003) Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology 229:838–846PubMedCrossRefGoogle Scholar
  17. 17.
    Kostura L, Kraitchman DL, Mackay AM, Pittenger MF, Bulte JW (2004) Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis. NMR Biomed 17:513–517PubMedCrossRefGoogle Scholar
  18. 18.
    Wu JC et al (2006) Transcriptional profiling of reporter genes used for molecular imaging of embryonic stem cell transplantation. Physiol Genomics 25:29–38PubMedCrossRefGoogle Scholar
  19. 19.
    Wu JC et al (2006) Proteomic analysis of reporter genes for molecular imaging of transplanted embryonic stem cells. Proteomics 6:6234–6249PubMedCrossRefGoogle Scholar
  20. 20.
    Cao F et al (2006) In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation 113:1005–1014PubMedCrossRefGoogle Scholar
  21. 21.
    Johansen J et al (2002) Evaluation of Tet-on system to avoid transgene down-regulation in ex vivo gene transfer to the CNS. Gene Ther 9:1291–1301PubMedCrossRefGoogle Scholar
  22. 22.
    Derouazi M et al (2006) Genetic characterization of CHO production host DG44 and derivative recombinant cell lines. Biochem Biophys Res Commun 340:1069–1077PubMedCrossRefGoogle Scholar
  23. 23.
    Olivares EC, Hollis RP, Chalberg TW, Meuse L, Kay MA, Calos MP (2002) Site-specific genomic integration produces therapeutic Factor IX levels in mice. Nat Biotechnol 20:1124–1128PubMedCrossRefGoogle Scholar
  24. 24.
    Krishnan M et al (2006) Effects of epigenetic modulation on reporter gene expression: implications for stem cell imaging. Faseb J 20:106–108PubMedGoogle Scholar
  25. 25.
    Nakamura Y, Yasuda T, Weisel RD, Li RK (2006) Enhanced cell transplantation: preventing apoptosis increases cell survival and ventricular function. Am J Physiol Heart Circ Physiol 291:H939–H947PubMedCrossRefGoogle Scholar
  26. 26.
    Muller-Ehmsen J et al (2002) Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. J Mol Cell Cardiol 34:107–116PubMedCrossRefGoogle Scholar
  27. 27.
    Yau TM, Kim C, Li G, Zhang Y, Weisel RD, Li RK (2005) Maximizing ventricular function with multimodal cell-based gene therapy. Circulation 112:I123–I128PubMedCrossRefGoogle Scholar
  28. 28.
    Himes N et al (2004) In vivo MRI of embryonic stem cells in a mouse model of myocardial infarction. Magn Reson Med 52:1214–1219PubMedCrossRefGoogle Scholar
  29. 29.
    Naylor LH (1999) Reporter gene technology: the future looks bright. Biochem Pharmacol 58:749–757PubMedCrossRefGoogle Scholar
  30. 30.
    Massoud TF, Gambhir SS (2003) Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 17:545–580PubMedCrossRefGoogle Scholar
  31. 31.
    Bos C et al (2004) In vivo MR imaging of intravascularly injected magnetically labeled mesenchymal stem cells in rat kidney and liver. Radiology 233:781–789PubMedCrossRefGoogle Scholar
  32. 32.
    Cunningham CH, Arai T, Yang PC, McConnell MV, Pauly JM, Conolly SM (2005) Positive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles. Magn Reson Med 53:999–1005PubMedCrossRefGoogle Scholar
  33. 33.
    Foltz WD, Cunningham CH, Mutsaers AJ, Conolly SM, Stewart DJ, Dick AJ (2006) Positive-contrast imaging in the rabbit hind-limb of transplanted cells bearing endocytosed superparamagnetic beads. J Cardiovasc Magn Reson 8:817–823PubMedCrossRefGoogle Scholar

Copyright information

© Academy of Molecular Imaging 2008

Authors and Affiliations

  • Ian Y. Chen
    • 1
    • 2
    • 5
    • 6
  • Joan M. Greve
    • 6
  • Olivier Gheysens
    • 1
    • 2
    • 5
    • 6
  • Jürgen K. Willmann
    • 1
    • 2
    • 5
    • 6
  • Martin Rodriguez-Porcel
    • 1
    • 2
    • 5
    • 6
  • Pauline Chu
    • 4
  • Ahmad Y. Sheikh
    • 1
    • 3
  • Anthony Z. Faranesh
    • 1
    • 5
  • Ramasamy Paulmurugan
    • 1
    • 2
    • 5
    • 6
  • Phillip C. Yang
    • 7
  • Joseph C. Wu
    • 1
    • 5
    • 7
  • Sanjiv S. Gambhir
    • 1
    • 2
    • 5
    • 6
  1. 1.Molecular Imaging Program at Stanford (MIPS)Stanford University School of MedicineStanfordUSA
  2. 2.Bio-X ProgramStanford University School of MedicineStanfordUSA
  3. 3.Department of CardiothoracicStanford University School of MedicineStanfordUSA
  4. 4.Department of Comparative MedicineStanford University School of MedicineStanfordUSA
  5. 5.Department of RadiologyStanford University School of MedicineStanfordUSA
  6. 6.Department of BioengineeringStanford University School of MedicineStanfordUSA
  7. 7.Department of Medicine, Division of Cardiovascular MedicineStanford University School of MedicineStanfordUSA

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