Advertisement

Basic Research in Cardiology

, Volume 103, Issue 2, pp 105–113 | Cite as

Imaging of stem cells using MRI

  • Dara L. KraitchmanEmail author
  • Jeff W. M. Bulte
REVIEW

Abstract

The administration of exogenous stem cells offers promise to regenerate many damaged organs. However, failures of these cellular therapies could be related to many issues, such as the type of stem cell, the dose of cellular therapeutic, dosing regime, and mode of delivery. The recent ability to directly label stem cells with magnetic resonance (MR) contrast agents provides a simple, straight-forward manner to monitor accurate cell delivery and track stem cells non-invasively in a serial manner. Provided here is an overview of the currently available MR-labeling methods, including direct non-specific labeling with contrast agents, indirect specific labeling with contrast agents, labeling with MRI reporter genes, and fluorine hot spot labeling. Several of these approaches have now been applied successfully in preclinical animal models of cardiovascular disease. Once properly implemented, future clinical trials may benefit greatly from imaging stem cells with MRI.

Key words

stem cells magnetic resonance imaging superparamagnetic iron oxides myocardial infarction reporter gene 

Notes

Conflict of Interest

The authors had a grant support from Siemens AG. They did receive research material by Bayer Schering Pharma AG and by Boston Scientific Corporation.

References

  1. 1.
    Albert TS, Kim RJ, Judd RM (2006) Assessment of no-reflow regions using cardiac MRI. Basic Res Cardiol 101:383–390PubMedCrossRefGoogle Scholar
  2. 2.
    Amado LC, Salrais AP, Schuleri KH, St. John ME, Xie J, Cattaneo SM, Durand DJ, Fitton T, Kuang JQ, Stewart GC, Lehrke S, Baumgartner WA, Martin BJ, Heldman AW, Hare JM (2005) Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci USA 102:11474–11479PubMedCrossRefGoogle Scholar
  3. 3.
    Anderson SA, Lee KK, Frank JA (2006) Gadolinium-fullerenol as a paramagnetic contrast agent for cellular imaging. Invest Radiol 41:332–338PubMedCrossRefGoogle Scholar
  4. 4.
    Arbab AS, Yocum GT, Rad AM, Khakoo AY, Fellowes V, Read EJ, Frank JA (2005) Labeling of cells with ferumoxides–protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells. NMR Biomed 18:553–559PubMedCrossRefGoogle Scholar
  5. 5.
    Bartunek J, Vanderheyden M, Vandekerckhove B, Mansour S, De Bruyne B, De Bondt P, Van Haute I, Lootens N, Heyndrickx G, Wijns W (2005) Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety. Circulation 112:I178–I183PubMedGoogle Scholar
  6. 6.
    Bulte JW (2005) Hot spot MRI emerges from the background. Nat Biotechnol 23:945–946PubMedCrossRefGoogle Scholar
  7. 7.
    Bulte JW, Arbab AS, Douglas T, Frank JA (2004) Preparation of magnetically labeled cells for cell tracking by magnetic resonance imaging. Methods Enzymol 386:275–299PubMedCrossRefGoogle Scholar
  8. 8.
    Bulte JW, Kraitchman DL (2004) Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 17:484–499PubMedCrossRefGoogle Scholar
  9. 9.
    Bulte JW, Kraitchman DL (2004) Monitoring cell therapy using iron oxide MR contrast agents. Curr Pharm Biotechnol 5:567–584PubMedCrossRefGoogle Scholar
  10. 10.
    Bulte JW, Kraitchman DL, Mackay AM, Pittenger MF, Arbab AS, Yocum GT, Kalish H, Jordan EK, Anderson SA, Khakoo AY, Read EJ, Frank JA (2004) Chondrogenic differentiation of mesenchymal stem cells is inhibited after magnetic labeling with ferumoxides. Blood 104:3410–3413PubMedCrossRefGoogle Scholar
  11. 11.
    Cao F, Lin S, Xie X, Ray P, Patel M, Zhang X, Drukker M, Dylla SJ, Connolly AJ, Chen X, Weissman IL, Gambhir SS, Wu JC (2006) In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation 113:1005–1014PubMedCrossRefGoogle Scholar
  12. 12.
    Caruthers SD, Neubauer AM, Hockett FD, Lamerichs R, Winter PM, Scott MJ, Gaffney PJ, Wickline SA, Lanza GM (2006) In vitro demonstration using 19F magnetic resonance to augment molecular imaging with paramagnetic perfluorocarbon nanoparticles at 1.5 Tesla. Invest Radiol 41:305–312PubMedCrossRefGoogle Scholar
  13. 13.
    Cohen B, Ziv K, Plaks V, Israely T, Kalchenko V, Harmelin A, Benjamin LE, Neeman M (2007) MRI detection of transcriptional regulation of gene expression in transgenic mice. Nat Med 13:498–503PubMedCrossRefGoogle Scholar
  14. 14.
    Cunningham CH, Arai T, Yang PC, McConnell MV, Pauly JM, Conolly SM (2005) Positive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles. Magn Reson Med 53:999–1005PubMedCrossRefGoogle Scholar
  15. 15.
    Daldrup-Link HE, Meier R, Rudelius M, Piontek G, Piert M, Metz S, Settles M, Uherek C, Wels W, Schlegel J, Rummeny EJ (2005) In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging. Eur Radiol 15:4–13PubMedCrossRefGoogle Scholar
  16. 16.
    de Silva R, Gutierrez LF, Raval AN, McVeigh ER, Ozturk C, Lederman RJ (2006) X-ray fused with magnetic resonance imaging (XFM) to target endomyocardial injections: validation in a swine model of myocardial infarction. Circulation 114:2342–2350PubMedCrossRefGoogle Scholar
  17. 17.
    de Vries IJ, Lesterhuis WJ, Barentsz JO, Verdijk P, van Krieken JH, Boerman OC, Oyen WJ, Bonenkamp JJ, Boezeman JB, Adema GJ, Bulte JW, Scheenen TW, Punt CJ, Heerschap A, Figdor CG (2005) Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol 23:1407–1413PubMedCrossRefGoogle Scholar
  18. 18.
    Dick AJ, Guttman MA, Raman VK, Peters DC, Pessanha BS, Hill JM, Smith S, Scott G, McVeigh ER, Lederman RJ (2003) Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in swine. Circulation 108:2899–2904PubMedCrossRefGoogle Scholar
  19. 19.
    Fernandez-Aviles F, San Roman JA, Garcia-Frade J, Fernandez ME, Penarrubia MJ, de la Fuente L, Gomez-Bueno M, Cantalapiedra A, Fernandez J, Gutierrez O, Sanchez PL, Hernandez C, Sanz R, Garcia-Sancho J, Sanchez A (2004) Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circ Res 95:742–748PubMedCrossRefGoogle Scholar
  20. 20.
    Frank JA, Miller BR, Arbab AS, Zywicke HA, Jordan EK, Lewis BK, Bryant LH Jr., Bulte JWM (2003) Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology 228:480–487PubMedCrossRefGoogle Scholar
  21. 21.
    Frank JA, Zywicke H, Jordan EK, Mitchell J, Lewis BK, Bryant LH Jr., Bulte JWM (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:S484–S487PubMedCrossRefGoogle Scholar
  22. 22.
    Garot J, Unterseeh T, Teiger E, Champagne S, Chazaud B, Gherardi R, Hittinger L, Gueret P, Rahmouni A, Sonnet C, Le Corvoisier P, Benhaiem-Sigaux N, Su J, Merlet P (2003) Magnetic resonance imaging of targeted catheter-based implantation of myogenic precursor cells into infarcted left ventricular myocardium. J Am Coll Cardiol 41:1841–1846PubMedCrossRefGoogle Scholar
  23. 23.
    Genove G, DeMarco U, Xu H, Goins WF, Ahrens ET (2005) A new transgene reporter for in vivo magnetic resonance imaging. Nat Med 11:450–454PubMedCrossRefGoogle Scholar
  24. 24.
    Giesel FL, Stroick M, Griebe M, Troster H, von der Lieth CW, Requardt M, Rius M, Essig M, Kauczor HU, Hennerici MG, Fatar M (2006) Gadofluorine m uptake in stem cells as a new magnetic resonance imaging tracking method: an in vitro and in vivo study. Invest Radiol 41:868–873PubMedCrossRefGoogle Scholar
  25. 25.
    Gilad AA, McMahon MT, Walczak P, Winnard PT Jr., Raman V, van Laarhoven HW, Skoglund CM, Bulte JW, van Zijl PC (2007) Artificial reporter gene providing MRI contrast based on proton exchange. Nat Biotechnol 25:217–219PubMedCrossRefGoogle Scholar
  26. 26.
    Hamano K, Nishida M, Hirata K, Mikamo A, Li TS, Harada M, Miura T, Matsuzaki M, Esato K (2001) Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results. Jpn Circ J 65:845–847PubMedCrossRefGoogle Scholar
  27. 27.
    Heyn C, Bowen CV, Rutt BK, Foster PJ (2005) Detection threshold of single SPIO-labeled cells with FIESTA. Magn Reson Med 53:312–320PubMedCrossRefGoogle Scholar
  28. 28.
    Hill JM, Dick AJ, Raman VK, Thompson RB, Yu ZX, Hinds KA, Pessanha BS, Guttman MA, Varney TR, Martin BJ, Dunbar CE, McVeigh ER, Lederman RJ (2003) Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 108:1009–1014PubMedCrossRefGoogle Scholar
  29. 29.
    Ito H, Komura N, Iwakura K, Kawano S, Okamura A, Fujii K (2006) Combination study of myocardial perfusion and left ventricular filling provides an excellent prediction of clinical outcomes in patients with reperfused myocardial infarction. Basic Res Cardiol 101:400–407PubMedCrossRefGoogle Scholar
  30. 30.
    Jacoby C, Molojavyi A, Flogel U, Merx MW, Ding Z, Schrader J (2006) Direct comparison of magnetic resonance imaging and conductance microcatheter in the evaluation of left ventricular function in mice. Basic Res Cardiol 101:87–95PubMedCrossRefGoogle Scholar
  31. 31.
    Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, Kalantzi M, Herbots L, Sinnaeve P, Dens J, Maertens J, Rademakers F, Dymarkowski S, Gheysens O, Van Cleemput J, Bormans G, Nuyts J, Belmans A, Mortelmans L, Boogaerts M, Van de Werf F (2006) Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367:113–121PubMedCrossRefGoogle Scholar
  32. 32.
    Kedziorek DA, Gilson WD, Stuber M, Huang G, Blush E, Cosby K, Korosoglou G, Soto AV, Bulte JWM, Hofmann LV, Kraitchman DL (2007) Mesenchymal stem cell therapy in a rabbit hindlimb ischemia model. J Am Coll Cardiol 49:362AGoogle Scholar
  33. 33.
    Kostura L, Kraitchman DL, Mackay AM, Pittenger MF, Bulte JW (2004) Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis. NMR Biomed 17:513–517PubMedCrossRefGoogle Scholar
  34. 34.
    Kraitchman DL, Heldman AW, Atalar E, Amado LC, Martin BJ, Pittenger MF, Hare JM, Bulte JW (2003) In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 107:2290–2293PubMedCrossRefGoogle Scholar
  35. 35.
    Kustermann E, Roell W, Breitbach M, Wecker S, Wiedermann D, Buehrle C, Welz A, Hescheler J, Fleischmann BK, Hoehn M (2005) Stem cell implantation in ischemic mouse heart: a high-resolution magnetic resonance imaging investigation. NMR Biomed 18:362–370PubMedCrossRefGoogle Scholar
  36. 36.
    Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K (2006) Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 355:1199–1209PubMedCrossRefGoogle Scholar
  37. 37.
    Mani V, Saebo KC, Itskovich V, Samber DD, Fayad ZA (2006) GRadient echo Acquisition for Superparamagnetic particles with Positive contrast (GRASP): sequence characterization in membrane and glass superparamagnetic iron oxide phantoms at 1.5T and 3T. Magn Reson Med 55:126–135PubMedCrossRefGoogle Scholar
  38. 38.
    Meyer GP, Wollert KC, Lotz J, Steffens J, Lippolt P, Fichtner S, Hecker H, Schaefer A, Arseniev L, Hertenstein B, Ganser A, Drexler H (2006) Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation 113:1287–1294PubMedCrossRefGoogle Scholar
  39. 39.
    Modo M, Cash D, Mellodew K, Williams SC, Fraser SE, Meade TJ, Price J, Hodges H (2002) Tracking transplanted stem cell migration using bifunctional, contrast agent-enhanced, magnetic resonance imaging. Neuroimage 17:803–811PubMedCrossRefGoogle Scholar
  40. 40.
    Partlow KC, Chen J, Brant JA, Neubauer AM, Meyerrose TE, Creer MH, Nolta JA, Caruthers SD, Lanza GM, Wickline SA (2007) 19F magnetic resonance imaging for stem/progenitor cell tracking with multiple unique perfluorocarbon nanobeacons. Faseb J 21(8):1647–1654Google Scholar
  41. 41.
    Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221PubMedCrossRefGoogle Scholar
  42. 42.
    Shapiro EM, Skrtic S, Sharer K, Hill JM, Dunbar CE, Koretsky AP (2004) MRI detection of single particles for cellular imaging. Proc Natl Acad Sci USA 101:10901–10906PubMedCrossRefGoogle Scholar
  43. 43.
    Soto AV, Gilson WD, Kedziorek D, Fritzges D, Izbudak I, Young RG, Pittenger MF, Bulte JW, Kraitchman DL (2006) MRI tracking of regional persistence of feridex-labeled mesenchymal stem cells in a canine myocardial infarction model. J Cardiovasc Magn Reson 8:89–90Google Scholar
  44. 44.
    Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106:1913–1918PubMedCrossRefGoogle Scholar
  45. 45.
    Stuber M, Gilson WD, Kedziorek D, Bulte JW, Kraitchman DL (2007) Positive contrast visualization of iron oxide-labeled stem cells using inversion recovery with ON-resonant water suppression (IRON). Magn Reson Med 58:1072–1077Google Scholar
  46. 46.
    Stuckey DJ, Carr CA, Martin-Rendon E, Tyler DJ, Willmott C, Cassidy PJ, Hale SJ, Schneider JE, Tatton L, Harding SE, Radda GK, Watt S, Clarke K (2006) Iron particles for noninvasive monitoring of bone marrow stromal cell engraftment into, and isolation of viable engrafted donor cells from, the heart. Stem Cells 24:1968–1975PubMedCrossRefGoogle Scholar
  47. 47.
    Tai JH, Foster P, Rosales A, Feng B, Hasilo C, Martinez V, Ramadan S, Snir J, Melling CW, Dhanvantari S, Rutt B, White DJ (2006) Imaging islets labeled with magnetic nanoparticles at 1.5 Tesla. Diabetes 55:2931–2938PubMedCrossRefGoogle Scholar
  48. 48.
    Tannous BA, Grimm J, Perry KF, Chen JW, Weissleder R, Breakefield XO (2006) Metabolic biotinylation of cell surface receptors for in vivo imaging. Nat Methods 3:391–396PubMedCrossRefGoogle Scholar
  49. 49.
    van den Bos EJ, Baks T, Moelker AD, Kerver W, van Geuns RJ, van der Giessen WJ, Duncker DJ, Wielopolski PA (2006) Magnetic resonance imaging of haemorrhage within reperfused myocardial infarcts: possible interference with iron oxide-labelled cell tracking? Eur Heart J 27:1620–1626PubMedCrossRefGoogle Scholar
  50. 50.
    Walczak P, Kedziorek D, Gilad AA, Lin S, Bulte JW (2005) Instant MR labeling of stem cells using magnetoelectroporation. Magn Reson Med 54(4):769–774PubMedCrossRefGoogle Scholar
  51. 51.
    Walter G, Barton ER, Sweeney HL (2000) Noninvasive measurement of gene expression in skeletal muscle. Proc Natl Acad Sci USA 97:5151–5155PubMedCrossRefGoogle Scholar
  52. 52.
    Winter PM, Morawski AM, Caruthers SD, Fuhrhop RW, Zhang H, Williams TA, Allen JS, Lacy EK, Robertson JD, Lanza GM, Wickline SA (2003) Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation 108:2270–2274PubMedCrossRefGoogle Scholar
  53. 53.
    Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364:141–148PubMedCrossRefGoogle Scholar
  54. 54.
    Zhu J, Zhou L, XingWu F (2006) Tracking neural stem cells in patients with brain trauma. N Engl J Med 355:2376–2378PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  1. 1.Russell H. Morgan Dept. of Radiology and Radiological ScienceJohns Hopkins University, School of MedicineBaltimoreUSA
  2. 2.Johns Hopkins UniversityBaltimoreUSA
  3. 3.Institute of NanoBiotechnology, Institute for Computational MedicineJohns Hopkins University, School of MedicineBaltimoreUSA
  4. 4.Dept. of Chemical and Biomolecular EngineeringJohns Hopkins University, School of MedicineBaltimoreUSA
  5. 5.Institute for Cell Engineering, Cellular Imaging Section and VascularBiology Program, Johns Hopkins University, School of MedicineBaltimoreUSA

Personalised recommendations