Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Technology Insight: in vivo cell tracking by use of MRI

Nature Clinical Practice Cardiovascular Medicine volume 3, pages 554–562 (2006)Cite this article

Abstract

Animal studies have shown some success in the use of stem cells of diverse origins to treat heart failure and ventricular dysfunction secondary to ischemic injury. The clinical use of these cells is, therefore, promising. In order to develop effective cell therapies, the location, distribution and long-term viability of these cells must be evaluated in a noninvasive manner. MRI of cells labeled with magnetically visible contrast agents after either direct injection or local or intravenous infusion has the potential to fulfill this goal. In this Review, techniques for labeling and imaging a variety of cells will be discussed. Particular attention will be given to the advantages and limitations of various contrast agents and passive and facilitated cell-labeling methods, as well as to imaging techniques that produce negative and positive contrast, and the effect on image quantification of compartmentalization of contrast agents within the cell.

Key Points

  • Local transplantation of stem cells has the potential to treat many cardiovascular diseases

  • Noninvasive tracking of labeled therapeutic cells will permit assessment of local engraftment

  • The labeling of therapeutic cells with imaging labels while maintaining cell viability requires use of both passive and facilitated transfection methods

  • MRI labels such as iron oxide nanoparticles provide strong MRI signal alteration while imparting low cellular toxic effects

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cultures of J744A. 1 macrophage-like murine cells stained with acridine orange (3,6-dimethylaminoacridine) for cytoplasm (pale orange) and nucleus (dark orange) visualization then counterstained with Prussian blue for iron visualization.
Figure 2: Micrographs showing uptake of iron oxide particles in cultured rat smooth-muscle cells.
Figure 3: Plot of T1 and T2 relaxation times versus superparamagnetic iron oxide concentration when uniformly distributed in agar gel with concentrations of iron ranging from 0 µmol/l to 0.273 µmol/l.
Figure 4: Test of positive-contrast imaging in vivo.
Figure 5: Representative hypointense or hyperintense lesions after myocardial infarction at injection sites (arrows) within 24 h of administration of mesenchymal stem cells labeled with superparamagnetic iron oxide, seen with various imaging methods.

Similar content being viewed by others

References

  1. Fernandez-Aviles F et al. (2004) Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circ Res 95: 742–748

    Article  CAS  Google Scholar 

  2. 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: 113–121

    Article  Google Scholar 

  3. Nagel E et al. (2003) Magnetic resonance perfusion measurements for the noninvasive detection of coronary artery disease. Circulation 108: 432–437

    Article  Google Scholar 

  4. Kim RJ et al. (1999) Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 100: 1992–2002

    Article  CAS  Google Scholar 

  5. Rajagopalan S et al. (2002) Magnetic resonance angiographic techniques for the diagnosis of arterial disease. Cardiol Clin 20: 501–512

    Article  Google Scholar 

  6. Frangioni JV et al. (2004) In vivo tracking of stem cells for clinical trials in cardiovascular disease. Circulation 110: 3378–3383

    Article  Google Scholar 

  7. Shen T et al. (1993) Monocrystalline iron oxide nanocompounds (MION): physicochemical properties. Magn Reson Med 29: 599–604

    Article  CAS  Google Scholar 

  8. Jung CW et al. (1995) Physical and chemical properties of superparamagnetic iron oxide MR contrast agents: ferumoxides, ferumoxtran, ferumoxsil. Magn Reson Imaging 13: 661–674

    Article  CAS  Google Scholar 

  9. Hinds KA et al. (2003) Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood 102: 867–872

    Article  CAS  Google Scholar 

  10. Cunningham CH et al. (2005) Positive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles. Magn Reson Med 53: 999–1005

    Article  CAS  Google Scholar 

  11. Mani V et al. (2006) Gradient echo acquisition for superparamagnetic particles with positive contrast (GRASP): sequence characterization in membrane and glass superparamagnetic iron oxide phantoms at 1.5 T and 3T. Magn Reson Med 55: 126–135

    Article  CAS  Google Scholar 

  12. Sun R et al. (2005) Physical and biological characterization of superparamagnetic iron oxide- and ultrasmall superparamagnetic iron oxide-labeled cells: a comparison. Invest Radiol 40: 504–513

    Article  Google Scholar 

  13. Daldrup-Link HE et al. (2005) Migration of iron oxide-labeled human hematopoietic progenitor cells in a mouse model: in vivo monitoring with 1.5-T MR imaging equipment. Radiology 234: 197–205

    Article  Google Scholar 

  14. Raynal I et al. (2004) Macrophage endocytosis of superparamagnetic iron oxide nanoparticles: mechanisms and comparison of ferumoxides and ferumoxtran-10. Invest Radiol 39: 56–63

    Article  CAS  Google Scholar 

  15. Ralph P et al. (1975) Reticulum cell sarcoma: an effector cell in antibody-dependent cell-mediated immunity. J Immunol 114: 898–905

    CAS  PubMed  Google Scholar 

  16. Fleige G et al. (2002) In vitro characterization of two different ultrasmall iron oxide particles for magnetic resonance cell tracking. Invest Radiol 37: 482–488

    Article  CAS  Google Scholar 

  17. Pratten MK and Lloyd JB et al. (1986) Pinocytosis and phagocytosis: the effect of size of a particulate substrate on its mode of capture by rat peritoneal macrophages cultured in vitro. Biochim Biophys Acta 881: 307–313

    Article  CAS  Google Scholar 

  18. Metz S et al. (2004) Capacity of human monocytes to phagocytose approved iron oxide MR contrast agents in vitro. Eur Radiol 14: 1851–1858

    Article  Google Scholar 

  19. Zelivyanskaya ML et al. (2003) Tracking superparamagnetic iron oxide labeled monocytes in brain by high-field magnetic resonance imaging. J Neurosci Res 73: 284–295

    Article  CAS  Google Scholar 

  20. Shapiro EM et al. (2005) Sizing it up: cellular MRI using micron-sized iron oxide particles. Magn Reson Med 53: 329–338

    Article  Google Scholar 

  21. Wu YL et al. (2006) In situ labeling of immune cells with iron oxide particles: an approach to detect organ rejection by cellular MRI. Proc Natl Acad Sci USA 103: 1852–1857

    Article  CAS  Google Scholar 

  22. de Vries IJ et al. (2005) Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol 23: 1407–1413

    Article  CAS  Google Scholar 

  23. Bulte JW et al. (1999) Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. Proc Natl Acad Sci USA 96: 15256–15261

    Article  CAS  Google Scholar 

  24. Jefferies WA et al. (1984) Transferrin receptor on endothelium of brain capillaries. Nature 312: 162–163

    Article  CAS  Google Scholar 

  25. Bulte JW et al. (2001) Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 19: 1141–1147

    Article  CAS  Google Scholar 

  26. Zhang ZY et al. (2000) High-generation polycationic dendrimers are unusually effective at disrupting anionic vesicles: membrane bending model. Bioconjug Chem 11: 805–814

    Article  CAS  Google Scholar 

  27. Wilhelm C et al. (2003) Intracellular uptake of anionic superparamagnetic nanoparticles as a function of their surface coating. Biomaterials 24: 1001–1011

    Article  CAS  Google Scholar 

  28. Riviere C et al. (2005) Iron oxide nanoparticle-labeled rat smooth muscle cells: cardiac MR imaging for cell graft monitoring and quantitation. Radiology 235: 959–967

    Article  Google Scholar 

  29. Bulte JW et al. (2004) Preparation of magnetically labeled cells for cell tracking by magnetic resonance imaging. Methods Enzymol 386: 275–299

    Article  CAS  Google Scholar 

  30. Strand BL et al. (2001) Poly-L-Lysine induces fibrosis on alginate microcapsules via the induction of cytokines. Cell Transplant 10: 263–275

    Article  CAS  Google Scholar 

  31. Kalish H et al. (2003) Combination of transfection agents and magnetic resonance contrast agents for cellular imaging: relationship between relaxivities, electrostatic forces, and chemical composition. Magn Reson Med 50: 275–282

    Article  CAS  Google Scholar 

  32. Arbab AS et al. (2004) Comparison of transfection agents in forming complexes with ferumoxides, cell labeling efficiency, and cellular viability. Mol Imaging 3: 24–32

    Article  CAS  Google Scholar 

  33. Arbab AS et al. (2004) Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. Blood 104: 1217–1223

    Article  CAS  Google Scholar 

  34. Arbab AS et al. (2005) Labeling of cells with ferumoxides-protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells. NMR Biomed 18: 553–559

    Article  CAS  Google Scholar 

  35. Arbab AS et al. (2006) Magnetic resonance imaging and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis. Stem Cells 24: 671–678

    Article  CAS  Google Scholar 

  36. Anderson SA et al. (2005) Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 105: 420–425

    Article  CAS  Google Scholar 

  37. 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: 838–846

    Article  Google Scholar 

  38. Yocum GT et al. (2005) Effect of human stem cells labeled with ferumoxides-poly-L-lysine on hematologic and biochemical measurements in rats. Radiology 235: 547–552

    Article  Google Scholar 

  39. Frank JA et al. (2004) Methods for magnetically labeling stem and other cells for detection by in vivo magnetic resonance imaging. Cytotherapy 6: 621–625

    Article  CAS  Google Scholar 

  40. Zhao M et al. (2002) Differential conjugation of tat peptide to superparamagnetic nanoparticles and its effect on cellular uptake. Bioconjug Chem 13: 840–844

    Article  CAS  Google Scholar 

  41. Vives E et al. (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem 272: 16010–16017

    Article  CAS  Google Scholar 

  42. Fawell S et al. (1994) Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci USA 91: 664–668

    Article  CAS  Google Scholar 

  43. Lewin M et al. (2000) Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat Biotechnol 18: 410–414

    Article  CAS  Google Scholar 

  44. Smits PC et al. (2003) Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol 42: 2063–2069

    Article  Google Scholar 

  45. van den Bos EJ et al. (2005) Functional assessment of myoblast transplantation for cardiac repair with magnetic resonance imaging. Eur J Heart Fail 7: 435–443

    Article  CAS  Google Scholar 

  46. Zhang Z et al. (2004) High-resolution magnetic resonance imaging of iron-labeled myoblasts using a standard 1.5-T clinical scanner. MAGMA 17: 201–209

    Article  CAS  Google Scholar 

  47. Walczak P et al. (2005) Instant MR labeling of stem cells using magnetoelectroporation. Magn Reson Med 54: 769–774

    Article  CAS  Google Scholar 

  48. Genove G et al. (2005) A new transgene reporter for in vivo magnetic resonance imaging. Nat Med 11: 450–454

    Article  CAS  Google Scholar 

  49. Billotey C et al. (2003) Cell internalization of anionic maghemite nanoparticles: quantitative effect on magnetic resonance imaging. Magn Reson Med 49: 646–654

    Article  CAS  Google Scholar 

  50. Bowen CV et al. (2002) Application of the static dephasing regime theory to superparamagnetic iron-oxide loaded cells. Magn Reson Med 48: 52–61

    Article  CAS  Google Scholar 

  51. Moore A et al. (2000) Tumoral distribution of long-circulating dextran-coated iron oxide nanoparticles in a rodent model. Radiology 214: 568–574

    Article  CAS  Google Scholar 

  52. Posse S (1992) Direct imaging of magnetic field gradients by group spin-echo selection. Magn Reson Med 25: 12–29

    Article  CAS  Google Scholar 

  53. Seppenwoolde JH et al. (2003) Passive tracking exploiting local signal conservation: the white marker phenomenon. Magn Reson Med 50: 784–790

    Article  Google Scholar 

  54. Kraitchman DL et al. (2003) In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 107: 2290–2293

    Article  Google Scholar 

  55. Krombach GA et al. (2005) MR-guided percutaneous intramyocardial injection with an MR-compatible catheter: feasibility and changes in T1 values after injection of extracellular contrast medium in pigs. Radiology 235: 487–494

    Article  Google Scholar 

  56. Hill JM et al. (2003) Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 108: 1009–1014

    Article  Google Scholar 

  57. Kraitchman DL et al. (2005) Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation 112: 1451–1461

    Article  Google Scholar 

  58. Zhang Z et al. (2005) In vitro imaging of single living human umbilical vein endothelial cells with a clinical 3.0-T MRI scanner. MAGMA 18: 175–185

    Article  CAS  Google Scholar 

  59. Heyn C et al. (2005) Detection threshold of single SPIO-labeled cells with FIESTA. Magn Reson Med 53: 312–320

    Article  Google Scholar 

  60. Shapiro EM et al. (2006) In vivo detection of single cells by MRI. Magn Reson Med 55: 242–249

    Article  Google Scholar 

  61. Martin ET et al. (2004) Magnetic resonance imaging and cardiac pacemaker safety at 1.5T. J Am Coll Cardiol 43: 1315–1324

    Article  Google Scholar 

  62. Roguin A et al. (2004) Modern pacemaker and implantable cardioverter/defibrillator systems can be magnetic resonance imaging safe: in vitro and in vivo assessment of safety and function at 1.5 T. Circulation 110: 475–482

    Article  Google Scholar 

Download references

Acknowledgements

We are saddened by the recent loss of our colleague Walter J Rogers, PhD, after a battle with leukemia. Dr Rogers was an exemplary friend and colleague who will be sorely missed at the University of Virginia and throughout the scientific community.

Author information

Authors and Affiliations

  1. Associate Professor of Radiology and Medicine,

    Walter J Rogers, Craig H Meyer & Christopher M Kramer

  2. Assistant Professor of Biomedical Engineering, at the University of Virginia Health System, Charlottesville, VA, USA

    Walter J Rogers, Craig H Meyer & Christopher M Kramer

Authors
  1. Walter J Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Craig H Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher M Kramer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher M Kramer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rogers, W., Meyer, C. & Kramer, C. Technology Insight: in vivo cell tracking by use of MRI. Nat Rev Cardiol 3, 554–562 (2006). https://doi.org/10.1038/ncpcardio0659

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio0659

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing