Advertisement

Journal of Neuro-Oncology

, Volume 107, Issue 2, pp 257–267 | Cite as

Imaging of human mesenchymal stromal cells: homing to human brain tumors

  • Lata G. Menon
  • John Pratt
  • Hong Wei Yang
  • Peter M. Black
  • Gregory A. Sorensen
  • Rona S. CarrollEmail author
Laboratory Investigation - Human/Animal Tissue

Abstract

Human mesenchymal stromal cells (hMSC) can be used as a drug delivery vehicle for the treatment of GBM. However, tracking the migration and distribution of these transplanted cells is necessary to interpret therapeutic efficacy. We compared three labeling techniques for their ability to track the migration of transplanted hMSC in an orthotopic mouse xenograft model. hMSC were labeled with three different imaging tags (fluorescence, luciferase or ferumoxide) for imaging by fluorescence, bioluminescence or magnetic resonance imaging (MRI), respectively. hMSC were labeled for all imaging modalities without the use of transfection agents. The labeling efficacy of the tags was confirmed, followed by in vitro and in vivo migration assays to track hMSC migration towards U87 glioma cells. Our results confirmed that the labeled hMSC retained their migratory ability in vitro, similar to unlabeled hMSC. In addition, labeled hMSC migrated towards the U87 tumor site, demonstrating their retention of tumor tropism. hMSC tumor tropism was confirmed by all three imaging modalities; however, MRI provides both real time assessment and the high resolution needed for clinical studies. Our findings suggest that ferumoxide labeling of hMSC is feasible, does not alter their migratory ability and allows detection by MRI. Non invasive tracking of transplanted therapeutic hMSC in the brain will allow further development of human cell based therapies.

Keywords

Glioblastoma Human bone marrow mesenchymal stromal cells Gene therapy Ferumoxide Magnetic resonance imaging 

Notes

Acknowledgements

We are grateful to Dr. Mark Johnson in the Department of Neurosurgery, Brigham and Women’s Hospital, (BWH) for reviewing the manuscript and expert technical advice. We thank Veronica Shi and Enzo Martinelli for the help with staining and cryosectioning. We would like to thank Dr. Myriam Armant, Center for Human Cell Therapy (at the Immune Disease Institute) for help with flow cytometry analysis of hMSC. We are thankful to Dr. Christian Farrar (A. A. Martinos Center for Biomedical Imaging) for helping us with MRI studies. We also would like to thank Dr Xiaoyin Xu, BICOR-Functional and Molecular Imaging Center at BWH, for his help with luciferase imaging experiments. This study was supported by grants from by Brain Science Foundation (BSF) to L.G.M.; Harvard Catalyst Grant to P.M.B., R.S.C., A.G.S and L.G.M., and by the US Public Health Service (T32 CA009502) to A.G.S.

Conflicts of interest

None.

References

  1. 1.
    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466PubMedCrossRefGoogle Scholar
  2. 2.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  3. 3.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507PubMedCrossRefGoogle Scholar
  4. 4.
    Menon LG, Kelly K, Yang HW, Kim SK, Black PM, Carroll RS (2009) Human bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy. Stem Cells 27:2320–2330PubMedCrossRefGoogle Scholar
  5. 5.
    Sasportas LS, Kasmieh R, Wakimoto H, Hingtgen S, van de Water JA, Mohapatra G, Figueiredo JL, Martuza RL, Weissleder R, Shah K (2009) Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc Natl Acad Sci U S A 106:4822–4827PubMedCrossRefGoogle Scholar
  6. 6.
    Fritz V, Jorgensen C (2008) Mesenchymal stem cells: an emerging tool for cancer targeting and therapy. Curr Stem Cell Res Ther 3:32–42PubMedCrossRefGoogle Scholar
  7. 7.
    Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, Andreeff M, Lang FF (2005) Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65:3307–3318PubMedGoogle Scholar
  8. 8.
    Yong RL, Shinojima N, Fueyo J, Gumin J, Vecil GG, Marini FC, Bogler O, Andreeff M, Lang FF (2009) Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas. Cancer Res 69:8932–8940PubMedCrossRefGoogle Scholar
  9. 9.
    Ryu CH, Park SH, Park SA, Kim SM, Lim JY, Jeong CH, Yoon WS, Oh WI, Sung YC, Jeun SS (2011) Gene therapy of intracranial glioma using interleukin 12-secreting human umbilical cord blood-derived mesenchymal stem cells. Hum Gene Ther 22(6):733–743Google Scholar
  10. 10.
    Choi SA, Hwang SK, Wang KC, Cho BK, Phi JH, Lee JY, Jung HW, Lee DH, Kim SK (2011) Therapeutic efficacy and safety of TRAIL-producing human adipose tissue-derived mesenchymal stem cells against experimental brainstem glioma. Neuro Oncol 13:61–69PubMedCrossRefGoogle Scholar
  11. 11.
    Meyerrose T, Olson S, Pontow S, Kalomoiris S, Jung Y, Annett G, Bauer G, Nolta JA (2010) Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Adv Drug Deliv Rev 62:1167–1174Google Scholar
  12. 12.
    Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY (2000) Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 97:12846–12851PubMedCrossRefGoogle Scholar
  13. 13.
    Kim SK, Cargioli TG, Machluf M, Yang W, Sun Y, Al-Hashem R, Kim SU, Black PM, Carroll RS (2005) PEX-producing human neural stem cells inhibit tumor growth in a mouse glioma model. Clin Cancer Res 11:5965–5970PubMedCrossRefGoogle Scholar
  14. 14.
    Kim SK, Kim SU, Park IH, Bang JH, Aboody KS, Wang KC, Cho BK, Kim M, Menon LG, Black PM, Carroll RS (2006) Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin Cancer Res 12:5550–5556PubMedCrossRefGoogle Scholar
  15. 15.
    Aboody KS, Najbauer J, Danks MK (2008) Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther 15:739–752PubMedCrossRefGoogle Scholar
  16. 16.
    Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, Kim YJ, Jo JY, Yoon EJ, Choi HJ, Kwon E (2011) Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev 20(8):1295–1296Google Scholar
  17. 17.
    Giordano A, Galderisi U, Marino IR (2007) From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol 211:27–35PubMedCrossRefGoogle Scholar
  18. 18.
    Salem HK, Thiemermann C (2009) Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 28:585–596Google Scholar
  19. 19.
    Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5:309–313PubMedCrossRefGoogle Scholar
  20. 20.
    Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP (2004) Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 94:92–95PubMedCrossRefGoogle Scholar
  21. 21.
    Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI, Lazarus HM (2000) Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 18:307–316PubMedGoogle Scholar
  22. 22.
    Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, Bulte JW, Petrou P, Ben-Hur T, Abramsky O, Slavin S (2010) Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 67:1187–1194Google Scholar
  23. 23.
    Kidd S, Spaeth E, Dembinski JL, Dietrich M, Watson K, Klopp A, Battula VL, Weil M, Andreeff M, Marini FC (2009) Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells 27:2614–2623PubMedCrossRefGoogle Scholar
  24. 24.
    Wang H, Cao F, De A, Cao Y, Contag C, Gambhir SS, Wu JC, Chen X (2009) Trafficking mesenchymal stem cell engraftment and differentiation in tumor-bearing mice by bioluminescence imaging. Stem Cells 27:1548–1558PubMedCrossRefGoogle Scholar
  25. 25.
    Condeelis J, Weissleder R (2010) In vivo imaging in cancer. Cold Spring Harb Perspect Biol 2:a003848Google Scholar
  26. 26.
    Willmann JK, Paulmurugan R, Rodriguez-Porcel M, Stein W, Brinton TJ, Connolly AJ, Nielsen CH, Lutz AM, Lyons J, Ikeno F, Suzuki Y, Rosenberg J, Chen IY, Wu JC, Yeung AC, Yock P, Robbins RC, Gambhir SS (2009) Imaging gene expression in human mesenchymal stem cells: from small to large animals. Radiology 252:117–127PubMedCrossRefGoogle Scholar
  27. 27.
    Hung SC, Deng WP, Yang WK, Liu RS, Lee CC, Su TC, Lin RJ, Yang DM, Chang CW, Chen WH, Wei HJ, Gelovani JG (2005) Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging. Clin Cancer Res 11:7749–7756PubMedCrossRefGoogle Scholar
  28. 28.
    Bindslev L, Haack-Sorensen M, Bisgaard K, Kragh L, Mortensen S, Hesse B, Kjaer A, Kastrup J (2006) Labelling of human mesenchymal stem cells with indium-111 for SPECT imaging: effect on cell proliferation and differentiation. Eur J Nucl Med Mol Imaging 33:1171–1177PubMedCrossRefGoogle Scholar
  29. 29.
    Chien LY, Hsiao JK, Hsu SC, Yao M, Lu CW, Liu HM, Chen YC, Yang CS, Huang DM (2011) In vivo magnetic resonance imaging of cell tropsim, trafficking mechanism, and therapeutic impact of human mesenchymal stem cells in a murine glioma model. Biomaterials 32:3275–3284Google Scholar
  30. 30.
    Foster PJ, Dunn EA, Karl KE, Snir JA, Nycz CM, Harvey AJ, Pettis RJ (2008) Cellular magnetic resonance imaging: in vivo imaging of melanoma cells in lymph nodes of mice. Neoplasia 10:207–216PubMedGoogle Scholar
  31. 31.
    Sun JH, Teng GJ, Ju SH, Ma ZL, Mai XL, Ma M (2008) MR tracking of magnetically labeled mesenchymal stem cells in rat kidneys with acute renal failure. Cell Transplant 17:279–290PubMedCrossRefGoogle Scholar
  32. 32.
    Heyn C, Ronald JA, Ramadan SS, Snir JA, Barry AM, MacKenzie LT, Mikulis DJ, Palmieri D, Bronder JL, Steeg PS, Yoneda T, MacDonald IC, Chambers AF, Rutt BK, Foster PJ (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 56:1001–1010PubMedCrossRefGoogle Scholar
  33. 33.
    Loebinger MR, Kyrtatos PG, Turmaine M, Price AN, Pankhurst Q, Lythgoe MF, Janes SM (2009) Magnetic resonance imaging of mesenchymal stem cells homing to pulmonary metastases using biocompatible magnetic nanoparticles. Cancer Res 69:8862–8867PubMedCrossRefGoogle Scholar
  34. 34.
    Wu X, Hu J, Zhou L, Mao Y, Yang B, Gao L, Xie R, Xu F, Zhang D, Liu J, Zhu J (2008) In vivo tracking of superparamagnetic iron oxide nanoparticle-labeled mesenchymal stem cell tropism to malignant gliomas using magnetic resonance imaging. Laboratory investigation. J Neurosurg 108:320–329PubMedCrossRefGoogle Scholar
  35. 35.
    Zhang Z, Jiang Q, Jiang F, Ding G, Zhang R, Wang L, Zhang L, Robin AM, Katakowski M, Chopp M (2004) In vivo magnetic resonance imaging tracks adult neural progenitor cell targeting of brain tumor. Neuroimage 23:281–287PubMedCrossRefGoogle Scholar
  36. 36.
    Thu MS, Najbauer J, Kendall SE, Harutyunyan I, Sangalang N, Gutova M, Metz MZ, Garcia E, Frank RT, Kim SU, Moats RA, Aboody KS (2009) Iron labeling and pre-clinical MRI visualization of therapeutic human neural stem cells in a murine glioma model. PLoS One 4:e7218Google Scholar
  37. 37.
    Berry CC, Wells S, Charles S, Curtis AS (2003) Dextran and albumin derivatised iron oxide nanoparticles: influence on fibroblasts in vitro. Biomaterials 24:4551–4557PubMedCrossRefGoogle Scholar
  38. 38.
    Reddy AM, Kwak BK, Shim HJ, Ahn C, Lee HS, Suh YJ, Park ES (2010) In vivo tracking of mesenchymal stem cells labeled with a novel chitosan-coated superparamagnetic iron oxide nanoparticles using 3.0T MRI. J Korean Med Sci 25:211–219Google Scholar
  39. 39.
    Arbab AS, Yocum GT, Kalish H, Jordan EK, Anderson SA, Khakoo AY, Read EJ, Frank JA (2004) Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. Blood 104:1217–1223PubMedCrossRefGoogle Scholar
  40. 40.
    Frank JA, Anderson SA, Kalsih H, Jordan EK, Lewis BK, Yocum GT, Arbab AS (2004) Methods for magnetically labeling stem and other cells for detection by in vivo magnetic resonance imaging. Cytotherapy 6:621–625PubMedCrossRefGoogle Scholar
  41. 41.
    Arbab AS, Bashaw LA, Miller BR, Jordan EK, Bulte JW, Frank JA (2003) Intracytoplasmic tagging of cells with ferumoxides and transfection agent for cellular magnetic resonance imaging after cell transplantation: methods and techniques. Transplantation 76:1123–1130PubMedCrossRefGoogle Scholar
  42. 42.
    Frank JA, Miller BR, Arbab AS, Zywicke HA, Jordan EK, Lewis BK, Bryant LH, Jr, Bulte JW (2003) Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology 228:480–487PubMedCrossRefGoogle Scholar
  43. 43.
    Kalish H, Arbab AS, Miller BR, Lewis BK, Zywicke HA, Bulte JW, Bryant LH, Jr, Frank JA (2003) Combination of transfection agents and magnetic resonance contrast agents for cellular imaging: relationship between relaxivities, electrostatic forces, and chemical composition. Magn Reson Med 50:275–282PubMedCrossRefGoogle Scholar
  44. 44.
    Menon LG, Picinich S, Koneru R, Gao H, Lin SY, Koneru M, Mayer-Kuckuk P, Glod J, Banerjee D (2007) Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells. Stem Cells 25:520–528PubMedCrossRefGoogle Scholar
  45. 45.
    Brooke G, Cook M, Blair C, Han R, Heazlewood C, Jones B, Kambouris M, Kollar K, McTaggart S, Pelekanos R, Rice A, Rossetti T, Atkinson K (2007) Therapeutic applications of mesenchymal stromal cells. Semin Cell Dev Biol 18:846–858PubMedCrossRefGoogle Scholar
  46. 46.
    Loebinger MR, Janes SM (2010) Stem cells as vectors for antitumour therapy. Thorax 65:362–369Google Scholar
  47. 47.
    Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F (2008) Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 15:730–738PubMedCrossRefGoogle Scholar
  48. 48.
    Doucette T, Rao G, Yang Y, Gumin J, Shinojima N, Bekele BN, Qiao W, Zhang W, Lang FF (2011) Mesenchymal stem cells display tumor-specific tropism in an RCAS/Ntv-a glioma model. Neoplasia 13:716–725Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Lata G. Menon
    • 1
  • John Pratt
    • 2
    • 3
  • Hong Wei Yang
    • 1
  • Peter M. Black
    • 1
  • Gregory A. Sorensen
    • 2
    • 3
  • Rona S. Carroll
    • 1
    Email author
  1. 1.Department of NeurosurgeryBrigham & Women’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.A. A. Martinos Center for Biomedical ImagingMassachusetts General HospitalBostonUSA
  3. 3.Harvard/MIT Division of Health Sciences and TechnologyBostonUSA

Personalised recommendations