Advertisement

Noninvasive Cell Tracking

  • Fabian Kiessling
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 185/2)

Abstract

Cell-based therapies may gain future importance in defeating different kinds of diseases, including cancer, immunological disorders, neurodegenerative diseases, cardiac infarction and stroke. In this context, the noninvasive localization of the transplanted cells and the monitoring of their migration can facilitate basic research on the underlying mechanism and improve clinical translation.

In this chapter, different ways to label and track cells in vivo are described. The oldest and only clinically established method is leukocyte scintigraphy, which enables a (semi)quantitative assessment of cell assemblies and, thus, the localization of inflammation foci. Noninvasive imaging of fewer or even single cells succeeds with MRI after labeling of the cells with (ultrasmall) superparamagentic iron oxide particles (SPIO and USPIO). However, in order to gain an acceptable signal-to-noise ratio, at a sufficiently high spatial resolution of the MR sequence to visualize a small amount of cells, experimental MR scanners working at high magnetic fields are usually required. Nevertheless, feasibility of clinical translation has been achieved by showing the localization of USPIO-labeled dendritic cells in cervical lymph nodes of patients by clinical MRI.

Cell-tracking approaches using optical methods are important for preclinical research. Here, cells are labeled either with fluorescent dyes or quantum dots, or transfected with plasmids coding for fluorescent proteins such as green fluorescent protein (GFP) or red fluorescent protein (RFP). The advantage of the latter approach is that the label does not get lost during cell division and, thus, makes imaging of proliferating transplanted cells (e.g., tumor cells) possible.

In summary, there are several promising options for noninvasive cell tracking, which have different strengths and limitations that should be considered when planning cell-tracking experiments.

Keywords

Green Fluorescent Protein Progenitor Cell Superparamagnetic Iron Oxide Iron Oxide Particle Cell Tracking 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ahrens ET, Feili-Hariri M, Xu H et al (2003) Receptor-mediated endocytosis of iron-oxide particles provides efficient labeling of dendritic cells for in vivo MR imaging. Magn Reson Med 49:1006–1013PubMedCrossRefGoogle Scholar
  2. Ahrens ET, Flores R, Xu H et al (2005) In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotechnol 23:983–987PubMedCrossRefGoogle Scholar
  3. Anderson SA, Shukaliak-Quandt J, Jordan EK et al (2004) Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis. Ann Neurol 55:654–659PubMedCrossRefGoogle Scholar
  4. Arbab AS, Pandit SD, Anderson SA et al (2006) MRI and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis. Stem Cells 24:671–678PubMedCrossRefGoogle Scholar
  5. Arvidsson A, Collin T, Kirik D et al (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970PubMedCrossRefGoogle Scholar
  6. Beckmann N, Cannet C, Fringeli-Tanner M et al (2003) Macrophage labeling by SPIO as an early marker of allograft chronic rejection in a rat model of kidney transplantation. Magn Reson Med 49:459–467PubMedCrossRefGoogle Scholar
  7. Billotey C, Wilhelm C, Devaud M et al (2003) Cell internalization of anionic maghemite nanoparticles: quantitative effect on magnetic resonance imaging. Magn Reson Med 49:646–654PubMedCrossRefGoogle Scholar
  8. Bulte JWM, Zhang S, van Gelderen P et al (1999) Neurotransplantation of magnetically labeled oligodendrocytes progenitors: MR tracking of cell migration and myelination. Proc Natl Acad Sci U S A 96:15256–15261PubMedCrossRefGoogle Scholar
  9. Bulte JWM, Douglas T, van Gelderen P et al (2001a). Cellular imaging using magnetodendrimers: application to human stem cells and neoplastic cells in vivo. Proc Int Soc Magn Reson Med 9:52Google Scholar
  10. Bulte JWM, Lu J, Zywicke H et al (2001b) 3D MR tracking of magnetically labeled embryonic stem cells transplanted in the contusion injured rat spinal cord. Proc Int Soc Magn Reson Med 9:130Google Scholar
  11. Bulte JWM, Douglas T, Witwer B et al (2001c) Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 19:1141–1147PubMedCrossRefGoogle Scholar
  12. Bulte JWM, Ben-Hur T, Miller BR et al (2003) MR microscopy of magnetically labeled neurospheres transplanted into the Lewis EAE rat brain. Magn Reson Med 50:201–205PubMedCrossRefGoogle Scholar
  13. Brenner W, Aicher A, Eckey T et al (2004) 111In-labeled CD34+ hematopoietic progenitor cells in a rat myocardial infarction model. J Nucl Med 45:512–518PubMedGoogle Scholar
  14. Cahill KS, Silver X, Gaidosh G et al (2003) Noninvasive monitoring and tracking of muscle stem cells. Proc Int Soc Magn Reson Med 11:368Google Scholar
  15. Chapon C, Franconi F, Lemaire L et al (2003) High field magnetic resonance imaging evaluation of superparamagnetic iron oxide nanoparticles in a permanent rat myocardial infarction. Invest Radiol 38:141–146PubMedCrossRefGoogle Scholar
  16. Contag CH, Jenkins D, Contag PR et al (2000) Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia 2:41–52PubMedCrossRefGoogle Scholar
  17. Daldrup-Link HE, Rudelius M, Oostendorp RAJ et al (2003) Targeting of hematopoietic progenitor cells with MR contrast agents. Radiology 228:760–767PubMedCrossRefGoogle Scholar
  18. Daldrup-Link HE, Rudelius M, Metz S et al (2004) Cell tracking with gadophrin-2: a bifunctional contrast agent for MR imaging, optical imaging, and fluorescence microscopy. Eur J Nucl Med Mol Imaging 31:1312–1321PubMedCrossRefGoogle Scholar
  19. De Vries IJ, Lesterhuis WJ, Barentsz JO et al (2005) Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring cellular therapy. Nat Biotechnol 23:1407–1413PubMedCrossRefGoogle Scholar
  20. Derfus AM, Chan WCW, Bhatia SN (2004) Probing the cytotoxicity of semiconductor quantum dots. Nano Letters 4:11–18CrossRefGoogle Scholar
  21. Dimmeler S, Zeiher AM, Schneider MD (2005) Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest 115:572–583PubMedGoogle Scholar
  22. Foster-Gareau P, Heyn C, Alejski A et al (2003) Imaging single mammalian cells with a 1.5 T clinical MRI scanner. Magn Reson Med 49:968–971PubMedCrossRefGoogle Scholar
  23. Frank JA, Zywicke H, Jordan EK, et al. (2002). Magnetic intracellular labeling of mammalian cells by combining (FDA-approved) superparamagnetic iron oxide MR contrast agents and commonly used transfection agents. Acad Radiol 9 Suppl 2:484–487CrossRefGoogle Scholar
  24. Frank JA, Miller BR, Arbab AS et al (2003) Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology 228:480–487PubMedCrossRefGoogle Scholar
  25. Franklin RJ, Blaschuk KL, Bearchell MC et al (1999) Magnetic resonance imaging of transplanted oligodendrocyte precursors in the rat brain. Neuroreport 10:3961–3965PubMedCrossRefGoogle Scholar
  26. Fleige G, Seeberger F, Laux D et al (2002) In vitro characterization of two different ultrasmall iron oxide particles for magnetic resonance cell tracking. Invest Radiol 37:482–488PubMedCrossRefGoogle Scholar
  27. Gao X, Cui Y, Levenson RM et al (2004) In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 22:969–976PubMedCrossRefGoogle Scholar
  28. Hakumaki JM, Savitt JM, Gearhart JD et al (2001) MRI detection of labeled neural progenitor cells in a mouse model of Parkinson’s disease. Dev Brain Res 132:43–44Google Scholar
  29. Harisinghani MG, Barentsz J, Hahn PF et al (2003) Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 348:2491–2499PubMedCrossRefGoogle Scholar
  30. Hill JM, Dick AJ, Raman VK et al (2005) Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 108:1009–1014CrossRefGoogle Scholar
  31. Hoehn M, Kuestermann E, Blunk J et al (2002) Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc Natl Acad Sci U S A 99:16267–16272PubMedCrossRefGoogle Scholar
  32. Hughes DK (2003) Nuclear medicine and infection detection: the relative effectiveness of imaging with 111In-oxine-, 99mTc-HMPAO-, and 99mTc-stannous fluoride colloid-labelled leucocytes and with 67Ga-citrate. J Nucl Med Technol 31:196–201PubMedGoogle Scholar
  33. Inoue H, Ohsawa I, Murakami T et al (2005). Development of new inbred transgenic strains of rats with LacZ or GFP. Biochem Biophys Res Commun 329:288–295PubMedCrossRefGoogle Scholar
  34. Josephson L, Tung CH, Moore A et al (1999) High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. Bioconjug Chem 10:186–191PubMedCrossRefGoogle Scholar
  35. Kircher MF, Allport JR, Graves EE et al (2003) In vivo high resolution three-dimensional imaging of antigen-specific cytotoxic T-lymphocyte trafficking to tumors. Cancer Res 63:6838–6846PubMedGoogle Scholar
  36. Kleinschnitz C, Bendszus M, Frank M (2003) In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging. J Cereb Blood Flow Metab 23:1356–1361PubMedCrossRefGoogle Scholar
  37. Kuestermann E, Roell W, Breitbach M et al (2005) Stem cell implantation in ischemic mouse heart: a high-resolution magnetic resonance imaging investigation. NMR Biomed 18:362–370CrossRefGoogle Scholar
  38. Kraitchman DL, Heldman AW, Atalar E et al (2003) In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 107:2290–2293PubMedCrossRefGoogle Scholar
  39. Lee I-H, Bulte JWM, Schweinhardt P et al (2004). In vivo magnetic resonance tracking of olfactory ensheathing glia grafted into the rat spinal cord. Exp Neurol 187:509–516PubMedCrossRefGoogle Scholar
  40. Lin WC, Pretlow TP, Pretlow TG et al (1990) Bacterial lacZ gene as a highly sensitive marker to detect micrometastasis formation during tumor progression. Cancer Res 50:2808–2817PubMedGoogle Scholar
  41. Lindvall O, Hagell P (2000) Clinical observation after neural transplantation in Parkinson’s disease. Prog Brain Res 127:299–320PubMedCrossRefGoogle Scholar
  42. Lindvall O, Bjoerklund A (2004) Cell Therapy in Parkinson’s Disease. NeuroRx 1:382–393PubMedCrossRefGoogle Scholar
  43. Lindvall O, Kokaia Z (2004) Recovery and rehabilitation in stroke: stem cells. Stroke 35: 2691–2694PubMedCrossRefGoogle Scholar
  44. Lewin M, Carlesso N, Tung CH, Tang XW, Cory D, Scadden DT, Weissleder R (2000) Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat Biotechnol 18:410–414PubMedCrossRefGoogle Scholar
  45. Losordo DW, Dimmeler S (2004) Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell based therapies. Circulation 109:2692–2697PubMedCrossRefGoogle Scholar
  46. McAfee JG, Subramanian G, Gagne G (1984) Techniques of leukocyte harvesting and labelling: problems and perspectives. Semin Nucl Med 2:83–106CrossRefGoogle Scholar
  47. Mothe AJ, Kulbatski I, van Bendegem RL et al (2005). Analysis of green fluorescent protein expression in transgenic rats for tracking transplanted neural stem/progenitor cells. J Histochem Cytochem 53:1215–1226PubMedCrossRefGoogle Scholar
  48. Moore A, Weissleder R, Bogdanov A Jr (1997) Uptake of dextrancoated monocrystalline iron oxides in tumor cells and macrophages. J Magn Reson Imaging 7:1140–1145PubMedCrossRefGoogle Scholar
  49. Nitin N, LaConte LEW, Zurkiya O et al (2004) Functionalization and peptide-based delivery of magnetic nanoparticles as an intracellular MRI contrast agent J Biol Inorg Chem 9:706–712PubMedCrossRefGoogle Scholar
  50. Onifer SM, White LA, Whitenmore SR et al (1993) In vitro labeling strategies for identifying primary neural tissue and a neuronal cell line after transplantation in the CNS. Cell Transplant 2:131–149PubMedGoogle Scholar
  51. Paczesny S, Ueno H, Fay J et al (2003) Dendritic cells as vectors for immunotherapy of cancer. Semin Cancer Biol 13:439–447PubMedCrossRefGoogle Scholar
  52. Parmiami G, Castelli C, Rivoltini L et al (2003) Immunotherapy of melanoma. Semin Cancer Biol 13:391–400CrossRefGoogle Scholar
  53. Schulz RB, Ripoll J, Ntziachristos V (2004). Experimental fluorescence tomography of tissues with noncontact measurements. IEEE Transact Med Imaging 23:492–500CrossRefGoogle Scholar
  54. Shapiro EM, Skrtic S, Koretsky A P (2005) Sizing it up: cellular MRI using micro-sized iron oxide particles. Magn Reson Med 53:329–338PubMedCrossRefGoogle Scholar
  55. Shichinohe H, Kuroda S, Lee JB (2004) In vivo tracking of bone marrow stromal cells transplanted into mice cerebral infarct by fluorescence optical imaging. Brain Res Prot 13:166–175CrossRefGoogle Scholar
  56. Sun R, Dittrich J, Le-Huu M et al (2005) Physical and biological characterization of superparamagnetic iron oxide- and ultrasmall superparamagnetic iron oxide-labeled cells: a comparison. Invest Radiol 40:504–513PubMedCrossRefGoogle Scholar
  57. Takahashi M, Hakamata Y, Murakami T et al (2003) Establishment of lacZ-transgenic rats: a tool for regenerative research in myocardium. Biochem Biophys Res Commun 305:904–908PubMedCrossRefGoogle Scholar
  58. Takusaburo E, Ogama N, Shimanuki H et al (2001) Effector mechanism and clinical response of BAK (BRM-activated killer) immuno-cell therapy for maintaining satisfactory QOL of advanced cancer patients utilizing CD56-positive NIE (neuro-immune-endocrine) cells. Microbiol Immunol 45:403–411Google Scholar
  59. Taupitz M, Schmitz S, Hamm B (2003) Superparamagnetic iron oxide particles: current state and future development. Rofo 175:752–765PubMedGoogle Scholar
  60. Voura EB, Jaiswal JK, Mattoussi H et al (2004) Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nat Med 10: 993–998PubMedCrossRefGoogle Scholar
  61. Vroemen M, Aigner L, Winkler J et al (2003) Adult neural progenitor cell grafts survive after acute spinal cord injury and integrate along axonal pathways. Eur J Neurosci 18:743–751PubMedCrossRefGoogle Scholar
  62. Vuu K, Xie J, McDonald MA et al (2005) Gadolinium-rhodamine nanoparticles for cell labeling and tracking via magnetic resonance and optical imaging. Bioconjug Chem 16:995–999PubMedCrossRefGoogle Scholar
  63. Walter GA, Cahill KS, Huard J et al (2004) Noninvasive monitoring of stem cell transfer for muscle disorders. Magn Reson Med 51:273–277PubMedCrossRefGoogle Scholar
  64. Weissleder R, Ntziachristos (2003) Shedding light onto live molecular targets. Nat Med 9:123–128PubMedCrossRefGoogle Scholar
  65. Weissleder R, Elizondo G, Wittenberg J et al (1990) Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology 175:489–493PubMedGoogle Scholar
  66. Weissleder R, Cheng HC, Bogdanova A et al (1997) Magnetically labeled cells can be detected by MR imaging. J Magn Reson Imaging 7:258–263PubMedCrossRefGoogle Scholar
  67. Yamamoto N, Jiang P, Yang M, et al. (2004). Cellular dynamics visualized in live cells in vitro and in vivo by differential dual-color nuclear-cytoplasic fluorescent-protein expression. Cancer Res 64:4251–4256PubMedCrossRefGoogle Scholar
  68. Wilhelm C, Billotey C, Roger J et al (2003) Intracellular uptake of anionic superparamagnetic nanoparticles as a function of their surface coating. Biomaterials 24:1001–1011PubMedCrossRefGoogle Scholar
  69. Yamauchi K, Yang M, Jiang P et al (2005) Real-time in vivo dual-color imaging of intracapillary cancer cell and nucleus deformation and migration. Cancer Res 65:4246–4252PubMedCrossRefGoogle Scholar
  70. Yeh TC, Zhang W, Ildstad ST et al (1993) Intracellular labeling of T-cells with superparamagnetic contrast agents. Magn Reson Med 30:617–625PubMedCrossRefGoogle Scholar
  71. Zelivyanskaya ML, Nelson JA, Poluektova L et al (2003) Tracking superparamagnetic iron oxide labeled monocytes in brain by high-field magnetic resonance imaging. J Neurosci Res 73: 284–295PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Fabian Kiessling
    • 1
  1. 1.Abteilung Medizinische Physik in der RadiologieDeutsches KrebsforschungszentrumHeidelberg

Personalised recommendations