Skip to main content

Advertisement

SpringerLink
Log in

In Vivo Imaging and Monitoring of Transplanted Stem Cells: Clinical Applications

  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Regenerative medicine using stem cells has appeared as a potential therapeutic alternative for coronary artery disease, and stem cell clinical studies are currently on their way. However, initial results of these studies have provided mixed information, in part because of the inability to correlate organ functional information with the presence/absence of transplanted stem cells. Recent advances in molecular biology and imaging have allowed the successful noninvasive monitoring of transplanted stem cells in the living subject. In this article, different imaging strategies (direct labeling, indirect labeling with reporter genes) to study the viability and biology of stem cells are discussed. In addition, the limitations of each approach and imaging modality (eg, single photon emission computed tomography, positron emission tomography, and MRI) and their requirements for clinical use are addressed. Use of these strategies will be critical as the different regenerative therapies are being tested for clinical use.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Orlic D, Kajstura J, Chimenti S, et al.: Bone marrow cells regenerate infarcted myocardium. Nature 2001, 410:701–705.

    Article  CAS  PubMed  Google Scholar 

  2. Gimble JM, Katz AJ, Bunnell BA: Adipose-derived stem cells for regenerative medicine. Circ Res 2007, 100:1249–1260.

    Article  CAS  PubMed  Google Scholar 

  3. Erbs S, Linke A, Schachinger V, et al.: Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. Circulation 2007, 116:366–374.

    Article  PubMed  Google Scholar 

  4. Lunde K, Solheim S, Aakhus S, et al.: Autologous stem cell transplantation in acute myocardial infarction: the ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects. Scand Cardiovasc J 2005, 39:150–158.

    Article  CAS  PubMed  Google Scholar 

  5. Wollert KC, Meyer GP, Lotz J, et al.: Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004, 364:141–148.

    Article  PubMed  Google Scholar 

  6. Dimmeler S, Zeiher AM: Cell therapy of acute myocardial infarction: open questions. Cardiology 2009, 113:155–160.

    Article  PubMed  Google Scholar 

  7. • Forrester JS, Makkar RR, Marban E: Long-term outcome of stem cell therapy for acute myocardial infarction: right results, wrong reasons. J Am Coll Cardiol 2009, 53:2270–2272. This editorial discusses the principal challenges encountered by the field of stem cell therapy for cardiac diseases.

  8. Bengel FM, Schachinger V, Dimmeler S: Cell-based therapies and imaging in cardiology. European journal of nuclear medicine and molecular imaging. 2005, 32(Suppl 2):S404–S416.

    Article  PubMed  Google Scholar 

  9. Thakur ML, Lavender JP, Arnot RN, et al.: Indium-111-labeled autologous leukocytes in man. J Nucl Med 1977, 18:1014–1021.

    CAS  PubMed  Google Scholar 

  10. Lin S, Xie X, Patel MR, et al.: Quantum dot imaging for embryonic stem cells. BMC Biotechnol 2007, 7:67.

    Article  PubMed  Google Scholar 

  11. Bos C, Delmas Y, Desmouliere A, et al.: In vivo MR imaging of intravascularly injected magnetically labeled mesenchymal stem cells in rat kidney and liver. Radiology 2004, 233:781–789.

    Article  PubMed  Google Scholar 

  12. Kraitchman DL, Heldman AW, Atalar E, et al.: In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 2003, 107:2290–2293.

    Article  PubMed  Google Scholar 

  13. Dick AJ, Guttman MA, Raman VK, et al.: Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in Swine. Circulation 2003, 108:2899–2904.

    Article  PubMed  Google Scholar 

  14. Massoud TF, Gambhir SS: Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 2003, 17:545–580.

    Article  CAS  PubMed  Google Scholar 

  15. Kraitchman DL, Tatsumi M, Gilson WD, et al.: Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation 2005, 112:1451–1461.

    Article  PubMed  Google Scholar 

  16. Li Z, Suzuki Y, Huang M, et al.: Comparison of reporter gene and iron particle labeling for tracking fate of human embryonic stem cells and differentiated endothelial cells in living subjects. Stem Cells 2008, 26:864–873.

    Article  CAS  PubMed  Google Scholar 

  17. Chen IY, Greve JM, Gheysens O, et al.: Comparison of optical bioluminescence reporter gene and superparamagnetic iron oxide MR contrast agent as cell markers for noninvasive imaging of cardiac cell transplantation. Mol Imaging Biol 2009, 11:178–187 .

    Article  PubMed  Google Scholar 

  18. Kang WJ, Kang HJ, Kim HS, et al.: Tissue distribution of 18F-FDG-labeled peripheral hematopoietic stem cells after intracoronary administration in patients with myocardial infarction. J Nucl Med 2006, 47:1295–1301.

    PubMed  Google Scholar 

  19. Chin BB, Nakamoto Y, Bulte JW, et al.: 111In oxine labelled mesenchymal stem cell SPECT after intravenous administration in myocardial infarction. Nucl Med Commun 2003, 24:1149–1154.

    Article  CAS  PubMed  Google Scholar 

  20. Wu JC, Tseng JR, Gambhir SS: Molecular imaging of cardiovascular gene products. J Nucl Cardiol 2004, 11:491–505.

    Article  PubMed  Google Scholar 

  21. Carr HM, Smyth JV, Rooney OB, et al.: Limitations of in-vitro labeling of endothelial cells with indium-111 oxine. Cell Transplant 1995, 4:291–296.

    Article  CAS  PubMed  Google Scholar 

  22. Zanzonico P, Koehne G, Gallardo HF, et al.: [131I]FIAU labeling of genetically transduced, tumor-reactive lymphocytes: cell-level dosimetry and dose-dependent toxicity. Eur J Nucl Med Mol Imaging 2006, 33:988–997.

    Article  CAS  PubMed  Google Scholar 

  23. Inubushi M, Tamaki N: Radionuclide reporter gene imaging for cardiac gene therapy. Eur J Nucl Med Mol Imaging 2007, 34(Suppl 1):S27–S33.

    Article  CAS  PubMed  Google Scholar 

  24. Phelps ME: Inaugural article: positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci USA 2000, 97:9226–9233.

    Article  CAS  PubMed  Google Scholar 

  25. Zhuo L, Sun B, Zhang CL, et al.: Live astrocytes visualized by green fluorescent protein in transgenic mice. Dev Biol 1997, 187:36–42.

    Article  CAS  PubMed  Google Scholar 

  26. Contag CH, Jenkins D, Contag PR, et al.: Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia 2000, 2:41–52.

    Article  CAS  PubMed  Google Scholar 

  27. Krishnan M, Park JM, Cao F, et al.: Effects of epigenetic modulation on reporter gene expression: implications for stem cell imaging. FASEB J 2006, 20:106–108.

    CAS  PubMed  Google Scholar 

  28. Cao F, Wagner RA, Wilson KD, et al.: Transcriptional and functional profiling of human embryonic stem cell-derived cardiomyocytes. PLoS One 2008, 3:e3474.

    Article  PubMed  Google Scholar 

  29. Wu JC, Cao F, Dutta S, et al.: Proteomic analysis of reporter genes for molecular imaging of transplanted embryonic stem cells. Proteomics 2006, 6:6234–6249.

    Article  CAS  PubMed  Google Scholar 

  30. Wang F, Dennis JE, Awadallah A, et al.: Transcriptional profiling of human mesenchymal stem cells transduced with reporter genes for imaging. Physiol Genomics 2009, 37:23–34.

    Article  PubMed  Google Scholar 

  31. Terrovitis J, Kwok KF, Lautamaki R, et al.: Ectopic expression of the sodium-iodide symporter enables imaging of transplanted cardiac stem cells in vivo by single-photon emission computed tomography or positron emission tomography. J Am Coll Cardiol 2008, 52:1652–1660.

    Article  PubMed  Google Scholar 

  32. Rodriguez-Porcel M, Gheysens O, Chen IY, et al.: Image-guided cardiac cell delivery using high-resolution small-animal ultrasound. Mol Ther 2005, 12:1142–1147.

    Article  CAS  PubMed  Google Scholar 

  33. Wu JC, Chen IY, Sundaresan G, et al.: Molecular imaging of cardiac cell transplantation in living animals using optical bioluminescence and positron emission tomography. Circulation 2003, 108:1302–1325.

    Google Scholar 

  34. Li Z, Wu JC, Sheikh AY, et al.: Differentiation, survival, and function of embryonic stem cell derived endothelial cells for ischemic heart disease. Circulation 2007, 116:I46–I54.

    Google Scholar 

  35. MacLaren DC, Gambhir SS, Satyamurthy N, et al.: Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals. Gene Ther 1999, 6:785–791.

    Article  CAS  PubMed  Google Scholar 

  36. Liang Q, Satyamurthy N, Barrio JR, et al.: Noninvasive, quantitative imaging in living animals of a mutant dopamine D2 receptor reporter gene in which ligand binding is uncoupled from signal transduction. Gene Ther 2001, 8:1490–1498.

    Article  CAS  PubMed  Google Scholar 

  37. Chen IY, Wu JC, Min JJ, et al.: Micro-positron emission tomography imaging of cardiac gene expression in rats using bicistronic adenoviral vector-mediated gene delivery. Circulation 2004, 109:1415–1420.

    Google Scholar 

  38. Kang JH, Lee DS, Paeng JC, et al.: Development of a sodium/iodide symporter (NIS)-transgenic mouse for imaging of cardiomyocyte-specific reporter gene expression. J Nucl Med 2005, 46:479–483.

    CAS  PubMed  Google Scholar 

  39. Cohen B, Dafni H, Meir G, et al.: Ferritin as an endogenous MRI reporter for noninvasive imaging of gene expression in C6 glioma tumors. Neoplasia 2005, 7:109–117.

    Article  CAS  PubMed  Google Scholar 

  40. Gilad AA, Winnard PT Jr, van Zijl PC, et al.: Developing MR reporter genes: promises and pitfalls. NMR Biomed 2007, 20:275–290.

    Article  CAS  PubMed  Google Scholar 

  41. Zinn KR, Chaudhuri TR: The type 2 human somatostatin receptor as a platform for reporter gene imaging. Eur J Nucl Med Mol Imaging 2002, 29:388–399.

    Article  CAS  PubMed  Google Scholar 

  42. Sharma V, Luker GD, Piwnica-Worms D: Molecular imaging of gene expression and protein function in vivo with PET and SPECT. J Magn Reson Imaging 2002, 16:336–351.

    Article  PubMed  Google Scholar 

  43. Zhernosekov K, Aschoff P, Filosofov D, et al.: Visualisation of a somatostatin receptor-expressing tumour with 67 Ga-DOTATOC SPECT. Eur J Nucl Med Mol Imaging 2005, 32:1129.

    Article  CAS  PubMed  Google Scholar 

  44. Alvarez-Maya I, Navarro-Quiroga I, Meraz-Rios MA, et al.: In vivo gene transfer to dopamine neurons of rat substantia nigra via the high-affinity neurotensin receptor. Mol Med 2001, 7:186–192.

    CAS  PubMed  Google Scholar 

  45. Lee CH, Wu CL, Shiau AL: Hypoxia-induced cytosine deaminase gene expression for cancer therapy. Hum Gene Ther 2007, 18:27–38.

    Article  CAS  PubMed  Google Scholar 

  46. Bloor CM, White FC, Roth DM: The pig as a model of myocardial ischemia and gradual coronary artery occlusion. In Swine as Models in Biomedical Research. Edited by Swindle MM, Moody DC, Phillips LD. Ames, Iowa: Iowa State University Press; 1992:163–175.

  47. Rodriguez-Porcel M, Brinton TJ, Chen IY, et al.: Reporter gene imaging following percutaneous delivery in swine moving toward clinical applications. J Am Coll Cardiol 2008, 51:595–597.

    Article  PubMed  Google Scholar 

  48. Bengel FM, Anton M, Richter T, et al.: Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer. Circulation 2003, 108:2127–2133.

    Article  CAS  PubMed  Google Scholar 

  49. •• Willmann JK, Paulmurugan R, Rodriguez-Porcel M, et al.: Imaging gene expression in human mesenchymal stem cells: from small to large animals. Radiology 2009, 252:117–127. In this study, the researchers used a PET reporter gene strategy to image, for the first time, stem cells after transplantation to the myocardium in a swine animal model.

  50. •• Yaghoubi SS, Jensen MC, Satyamurthy N, et al.: Noninvasive detection of therapeutic cytolytic T cells with 18F-FHBG PET in a patient with glioma. Nat Clin Pract Oncol 2009, 6:53–58. The study by Yaghoubi et al. constitutes the first to image transplanted cells in a patient noninvasively. In this study, lymphocytic T cells, carrying a PET reporter gene, were delivered to patients with glioma and cell status imaged after the administration of the appropriate reporter probe.

  51. Rodriguez-Porcel M, Wu JC, Gambhir SS: Molecular imaging of stem cells. StemBook 2009. Available at http://www.stembook.org/node/603. Accessed November 2009.

Download references

Acknowledgments

US National Institutes of Health HL88048 and the Mayo Foundation Scholarship Program.

Disclosure

No potential conflict of interest relevant to this article was reported.

Author information

Authors and Affiliations

  1. Stabile 4-56, Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Martin Rodriguez-Porcel

Authors
  1. Martin Rodriguez-Porcel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Rodriguez-Porcel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodriguez-Porcel, M. In Vivo Imaging and Monitoring of Transplanted Stem Cells: Clinical Applications. Curr Cardiol Rep 12, 51–58 (2010). https://doi.org/10.1007/s11886-009-0073-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11886-009-0073-1

Keywords

Search

Navigation