Skip to main content

Advertisement

SpringerLink
Log in

The Use of Cellular Magnetic Resonance Imaging to Track the Fate of Iron-Labeled Multipotent Stromal Cells after Direct Transplantation in a Mouse Model of Spinal Cord Injury

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The objective of this study was to track the fate of iron-labeled, multipotent stromal cells (MSC) after their direct transplantation into mice with spinal cord injuries using magnetic resonance imaging (MRI).

Procedures

Mice with spinal cord injuries received a direct transplant of (1) live MSC labeled with micron-sized iron oxide particles (MPIO); (2) dead, MPIO-labeled MSC; (3) unlabeled MSC; or (4) free MPIO and were imaged at 3 T for 6 weeks after transplantation.

Results

Live, iron-labeled MSC appeared as a well-defined region of signal loss in the mouse spinal cord at the site of transplant. However, the MR appearance of dead, iron-labeled MSC and free iron particles was similar and persisted for the 6 weeks of the study.

Conclusions

Iron-labeled stem cells can be detected and monitored in vivo after direct transplantation into the injured spinal cord of mice. However, the fate of the iron label is not clear. Our investigation indicates that caution should be taken when interpreting MR images after direct transplantation of iron-labeled cells.

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. Dousset V, Tourdias T, Brochet B, Boiziau C, Petry KG (2008) How to trace stem cells for MRI evaluation? J Neurol Sci 265(1–2):122–126

    Article  PubMed  CAS  Google Scholar 

  2. Foster PJ, Dunn EA, Karl KE et al (2008) Cellular magnetic resonance imaging: in vivo imaging of melanoma cells in lymph nodes of mice. Neoplasia 10(3):207–216

    PubMed  CAS  Google Scholar 

  3. Heyn C, Ronald JA, Ramadan SS et al (2006) In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magn Reson Med 56(5):1001–1010

    Article  PubMed  Google Scholar 

  4. Medarova Z, Tsai S, Evgenov N, Santamaria P, Moore A (2008) In vivo imaging of a diabetogenic CD8+ T cell response during type 1 diabetes progression. Magn Reson Med 59(4):712–720

    Article  PubMed  Google Scholar 

  5. Song M, Kim Y, Ryu S et al (2009) MRI tracking of intravenously transplanted human neural stem cells in rat focal ischemia model. Neurosci Res 64(2):235–239

    Article  PubMed  Google Scholar 

  6. Sun JH, Teng GJ, Ju SH et al (2008) MR tracking of magnetically labeled mesenchymal stem cells in rat kidneys with acute renal failure. Cell Transplant 17(3):279–290

    Article  PubMed  Google Scholar 

  7. Walczak P, Zhang J, Gilad AA et al (2008) Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke 39(5):1569–1574

    Article  PubMed  CAS  Google Scholar 

  8. Wu YL, Ye Q, Foley LM 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 U S A 103(6):1852–1857

    Article  PubMed  CAS  Google Scholar 

  9. Heyn C, Bowen CV, Rutt BK, Foster PJ (2005) Detection threshold of single SPIO-labeled cells with FIESTA. Magn Reson Med 53(2):312–320

    Article  PubMed  Google Scholar 

  10. Bulte JW, 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(1):201–205

    Article  PubMed  Google Scholar 

  11. Chang NK, Jeong YY, Park JS et al (2008) Tracking of neural stem cells in rats with intracerebral hemorrhage by the use of 3 T MRI. Korean J Radiol 9(3):196–204

    Article  PubMed  Google Scholar 

  12. Jendelova P, Herynek V, Urdzikova L et al (2004) Magnetic resonance tracking of transplanted bone marrow and embryonic stem cells labeled by iron oxide nanoparticles in rat brain and spinal cord. J Neurosci Res 76(2):232–243

    Article  PubMed  CAS  Google Scholar 

  13. Lee IH, Bulte JW, Schweinhardt P et al (2004) In vivo magnetic resonance tracking of olfactory ensheathing glia grafted into the rat spinal cord. Exp Neurol 187(2):509–516

    Article  PubMed  Google Scholar 

  14. Lepore AC, Walczak P, Rao MS, Fischer I, Bulte JW (2006) MR imaging of lineage-restricted neural precursors following transplantation into the adult spinal cord. Exp Neurol 201(1):49–59

    Article  PubMed  CAS  Google Scholar 

  15. Sykova, E. and Jendelova, P. Migration, fate and in vivo imaging of adult stem cells in the CNS. Cell Death Differ, 2007.

  16. Sykova E, Jendelova P (2007) In vivo tracking of stem cells in brain and spinal cord injury. Prog Brain Res 161:367–383

    Article  PubMed  CAS  Google Scholar 

  17. Cizkova D, Rosocha J, Vanicky I, Jergova S, Cizek M (2006) Transplants of human mesenchymal stem cells improve functional recovery after spinal cord injury in the rat. Cell Mol Neurobiol 26(7–8):1167–1180

    PubMed  Google Scholar 

  18. Koshizuka S, Okada S, Okawa A et al (2004) Transplanted hematopoietic stem cells from bone marrow differentiate into neural lineage cells and promote functional recovery after spinal cord injury in mice. J Neuropathol Exp Neurol 63(1):64–72

    PubMed  Google Scholar 

  19. Louro J, Pearse DD (2008) Stem and progenitor cell therapies: recent progress for spinal cord injury repair. Neurol Res 30(1):5–16

    Article  PubMed  CAS  Google Scholar 

  20. Okano H, Sakaguchi M, Ohki K, Suzuki N, Sawamoto K (2007) Regeneration of the central nervous system using endogenous repair mechanisms. J Neurochem 102(5):1459–1465

    Article  PubMed  CAS  Google Scholar 

  21. Okano H, Sawamoto K (2008) Neural stem cells: involvement in adult neurogenesis and CNS repair. Philos Trans R Soc Lond B Biol Sci 363(1500):2111–2122

    Article  PubMed  Google Scholar 

  22. Jackson L, Jones DR, Scotting P, Sottile V (2007) Adult mesenchymal stem cells: differentiation potential and therapeutic applications. J Postgrad Med 53(2):121–127

    Article  PubMed  CAS  Google Scholar 

  23. Tropel P, Platet N, Platel JC et al (2006) Functional neuronal differentiation of bone marrow-derived mesenchymal stem cells. Stem Cells 24(12):2868–2876

    Article  PubMed  CAS  Google Scholar 

  24. Rapalino O, Lazarov-Spiegler O, Agranov E et al (1998) Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 4(7):814–821

    Article  PubMed  CAS  Google Scholar 

  25. Schwartz M, Lazarov-Spiegler O, Rapalino O et al (1999) Potential repair of rat spinal cord injuries using stimulated homologous macrophages. Neurosurgery 44(5):1041–1045, discussion 1045-1046

    Article  PubMed  CAS  Google Scholar 

  26. Schwartz M (2001) Immunological approaches to the treatment of spinal cord injury. BioDrugs 15(9):585–593

    Article  PubMed  CAS  Google Scholar 

  27. Mikami Y, Okano H, Sakaguchi M et al (2004) Implantation of dendritic cells in injured adult spinal cord results in activation of endogenous neural stem/progenitor cells leading to de novo neurogenesis and functional recovery. J Neurosci Res 76(4):453–465

    Article  PubMed  CAS  Google Scholar 

  28. McDonald JW, Liu XZ, Qu Y et al (1999) Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5(12):1410–1412

    Article  PubMed  CAS  Google Scholar 

  29. Ogawa Y, Sawamoto K, Miyata T et al (2002) Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res 69(6):925–933

    Article  PubMed  CAS  Google Scholar 

  30. Chopp M, Zhang XH, Li Y et al (2000) Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation. NeuroReport 11(13):3001–3005

    Article  PubMed  CAS  Google Scholar 

  31. Hofstetter CP, Schwarz EJ, Hess D et al (2002) Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci USA 99(4):2199–2204

    Article  PubMed  CAS  Google Scholar 

  32. Ohta M, Suzuki Y, Noda T et al (2004) Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation. Exp Neurol 187(2):266–278

    Article  PubMed  CAS  Google Scholar 

  33. Zurita M, Vaquero J (2004) Functional recovery in chronic paraplegia after bone marrow stromal cells transplantation. NeuroReport 15(7):1105–1108

    Article  PubMed  Google Scholar 

  34. Chernykh ER, Stupak VV, Muradov GM et al (2007) Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients. Bull Exp Biol Med 143(4):543–547

    Article  PubMed  CAS  Google Scholar 

  35. Deda H, Inci MC, Kurekci AE et al (2008) Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy 10(6):565–574

    Article  PubMed  CAS  Google Scholar 

  36. Moviglia, G.A., Varela, G., Brizuela, J.A.et al. 2009 Case report on the clinical results of a combined cellular therapy for chronic spinal cord injured patients. Spinal Cord

  37. Sykova E, Homola A, Mazanec R et al (2006) Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 15(8–9):675–687

    Article  PubMed  Google Scholar 

  38. Callera F, de Melo CM (2007) Magnetic resonance tracking of magnetically labeled autologous bone marrow CD34+ cells transplanted into the spinal cord via lumbar puncture technique in patients with chronic spinal cord injury: CD34+ cells' migration into the injured site. Stem Cells Dev 16(3):461–466

    Article  PubMed  Google Scholar 

  39. Terrovitis J, Stuber M, Youssef A et al (2008) Magnetic resonance imaging overestimates ferumoxide-labeled stem cell survival after transplantation in the heart. Circulation 117(12):1555–1562

    Article  PubMed  Google Scholar 

  40. Jacob JE, Gris P, Fehlings MG, Weaver LC, Brown A (2003) Autonomic dysreflexia after spinal cord transection or compression in 129 Sv, C57BL, and Wallerian degeneration slow mutant mice. Exp Neurol 183(1):136–146

    Article  PubMed  CAS  Google Scholar 

  41. Joshi M, Fehlings MG (2002) Development and characterization of a novel, graded model of clip compressive spinal cord injury in the mouse: Part 1. Clip design, behavioral outcomes, and histopathology. J Neurotrauma 19(2):175–190

    Article  PubMed  Google Scholar 

  42. Koda M, Okada S, Nakayama T et al (2005) Hematopoietic stem cell and marrow stromal cell for spinal cord injury in mice. NeuroReport 16(16):1763–1767

    Article  PubMed  Google Scholar 

  43. Kobayashi H, Kawamoto S, Star RA et al (2003) Micro-magnetic resonance lymphangiography in mice using a novel dendrimer-based magnetic resonance imaging contrast agent. Cancer Res 63(2):271–276

    PubMed  CAS  Google Scholar 

  44. Rosset A, Spadola L, Ratib O (2004) OsiriX: an open-source software for navigating in multidimensional DICOM images. J Digit Imaging 17(3):205–216

    Article  PubMed  Google Scholar 

  45. Blight AR (2002) Miracles and molecules—progress in spinal cord repair. Nat Neurosci 5(Suppl):1051–1054

    Article  PubMed  CAS  Google Scholar 

  46. Zhou B, Shan H, Li D (1996) MR tracking of magnetically labeled mesenchymal stem cells in rats with liver fibrosis. Magn Reson Imaging 28(3):394–399

    Article  Google Scholar 

  47. Politi LS, Bacigaluppi M, Brambilla E et al (2007) Magnetic-resonance-based tracking and quantification of intravenously injected neural stem cell accumulation in the brains of mice with experimental multiple sclerosis. Stem Cells 25(10):2583–2592

    Article  PubMed  Google Scholar 

  48. Arbab AS, Janic B, Knight RA et al (2008) Detection of migration of locally implanted AC133+ stem cells by cellular magnetic resonance imaging with histological findings. FASEB J 22(9):3234–3246

    Article  PubMed  CAS  Google Scholar 

  49. Magnitsky S, Walton RM, Wolfe JH, Poptani H (2008) Magnetic resonance imaging detects differences in migration between primary and immortalized neural stem cells. Acad Radiol 15(10):1269–1281

    Article  PubMed  Google Scholar 

  50. McAteer MA, Sibson NR, von Zur Muhlen C et al (2007) In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nat Med 13(10):1253–1258

    Article  PubMed  CAS  Google Scholar 

  51. Bernas LM, Foster PJ, Rutt BK (2007) Magnetic resonance imaging of in vitro glioma cell invasion. J Neurosurg 106(2):306–313

    Article  PubMed  CAS  Google Scholar 

  52. Cromer Berman, S.M., Gilad, A.A., Bulte, J.W. and Walczak, P. Long-Term MR Imaging of Immunocompetent and Immunodeficient Mice Reveals Distinct Differences in Contrast Clearance in the Brain. Joint Annual Meeting ISMRM-ESMRMB Stockholm, Sweden, 2010 (Abstract).

  53. Pawelczyk E, Jordan EK, Balakumaran A et al (2009) In vivo transfer of intracellular labels from locally implanted bone marrow stromal cells to resident tissue macrophages. Plos One 4(8):e6712

    Article  PubMed  Google Scholar 

  54. Moloney, T.C., Dockery, P., Windebank, A.J.et al. Survival and Immunogenicity of Mesenchymal Stem Cells From the Green Fluorescent Protein Transgenic Rat in the Adult Rat Brain. Neurorehabil Neural Repair.

  55. Winter EM, Hogers B, van der Graaf LM et al (2010) Cell tracking using iron oxide fails to distinguish dead from living transplanted cells in the infarcted heart. Magn Reson Med 63(3):817–821

    Article  PubMed  CAS  Google Scholar 

  56. Jackson J, Chapon C, Jones W et al (2009) In vivo multimodal imaging of stem cell transplantation in a rodent model of Parkinson's disease. J Neurosci Methods 183(2):141–148

    Article  PubMed  Google Scholar 

  57. Sykova E, Jendelova P (2006) Magnetic resonance tracking of transplanted stem cells in rat brain and spinal cord. Neurodegener Dis 3(1–2):62–67

    PubMed  Google Scholar 

  58. Dunning MD, Kettunen MI, Ffrench Constant C, Franklin RJ, Brindle KM (2006) Magnetic resonance imaging of functional Schwann cell transplants labelled with magnetic microspheres. Neuroimage 31(1):172–180

    Article  PubMed  Google Scholar 

  59. Higuchi T, Anton M, Dumler K et al (2009) Combined reporter gene PET and iron oxide MRI for monitoring survival and localization of transplanted cells in the rat heart. J Nucl Med 50(7):1088–1094

    Article  PubMed  CAS  Google Scholar 

  60. Amsalem Y, Mardor Y, Feinberg MS et al (2007) Iron-oxide labeling and outcome of transplanted mesenchymal stem cells in the infarcted myocardium. Circulation 116(11 Suppl):I38–I45

    PubMed  CAS  Google Scholar 

  61. Cao AH, Shi HJ, Zhang Y, Teng GJ (2009) In vivo tracking of dual-labeled mesenchymal stem cells homing into the injured common carotid artery. Anat Rec (Hoboken) 292(10):1677–1683

    Google Scholar 

  62. Lee ES, Chan J, Shuter B et al (2009) Microgel iron oxide nanoparticles for tracking human fetal mesenchymal stem cells through magnetic resonance imaging. Stem Cells 27(8):1921–1931

    Article  PubMed  CAS  Google Scholar 

  63. Jirak D, Kriz J, Strzelecki M et al (2009) Monitoring the survival of islet transplants by MRI using a novel technique for their automated detection and quantification. Magma 22(4):257–265

    Article  PubMed  CAS  Google Scholar 

  64. Dekaban GA, Snir J, Shrum B et al (2009) Semiquantitation of mouse dendritic cell migration in vivo using cellular MRI. J Immunother 32(3):240–251

    Article  PubMed  Google Scholar 

  65. Pawelczyk E, Arbab AS, Chaudhry A et al (2008) In vitro model of bromodeoxyuridine or iron oxide nanoparticle uptake by activated macrophages from labeled stem cells: implications for cellular therapy. Stem Cells 26(5):1366–1375

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Elizabeth Dunn for technical assistance, Vasiliki Economopoulos for assistance with data analysis, Dr. Andrew Alejski for technical support with the MRI hardware, and Judy Sholdice and Dr. Susan Koval at the Transmission Electron Microscopy Facility in the Department of Microbiology and Immunology at The University of Western Ontario. Funding provided by the Ontario Neurotrauma Foundation (LG) and the Canadian Institutes of Health Research (PF).

Conflict of Interest

The authors have no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada

    Laura E. Gonzalez-Lara & Paula J. Foster

  2. Robarts Research Institute, London, Ontario, Canada

    Laura E. Gonzalez-Lara, Xiaoyun Xu, Klara Hofstetrova, Anna Pniak, Yuhua Chen, Catherine D. McFadden, Francisco M. Martinez-Santiesteban, Arthur Brown & Paula J. Foster

  3. Richard M. Lucas Center for Imaging, Radiology Department, Stanford University, Stanford, California, USA

    Brian K. Rutt

  4. Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario, Canada

    Arthur Brown

Authors
  1. Laura E. Gonzalez-Lara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoyun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Klara Hofstetrova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Pniak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuhua Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Catherine D. McFadden
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francisco M. Martinez-Santiesteban
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Brian K. Rutt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Arthur Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Paula J. Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura E. Gonzalez-Lara.

Additional information

Manuscript Category and Significance: This is an original article reporting on the first study to use in vivo MRI to monitor the fate of stem cells after their direct transplantation into the injured spinal cord in mice. Our investigation indicates that caution should be taken when interpreting MR images after direct transplantation of iron-labeled cells. Cell death and subsequent phagocytosis of iron particles by macrophages may render the MRI signal nonspecific for tracking transplanted cells for long periods of time.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gonzalez-Lara, L.E., Xu, X., Hofstetrova, K. et al. The Use of Cellular Magnetic Resonance Imaging to Track the Fate of Iron-Labeled Multipotent Stromal Cells after Direct Transplantation in a Mouse Model of Spinal Cord Injury. Mol Imaging Biol 13, 702–711 (2011). https://doi.org/10.1007/s11307-010-0393-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-010-0393-y

Key Words

Search

Navigation