Skip to main content

Advertisement

Log in

In vivo Cell Tracking Using Non-invasive Imaging of Iron Oxide-Based Particles with Particular Relevance for Stem Cell-Based Treatments of Neurological and Cardiac Disease

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

A Correction to this article was published on 15 June 2021

This article has been updated

Abstract

Stem cell-based therapeutics is a rapidly developing field associated with a number of clinical challenges. One such challenge lies in the implementation of methods to track stem cells and stem cell-derived cells in experimental animal models and in the living patient. Here, we provide an overview of cell tracking in the context of cardiac and neurological disease, focusing on the use of iron oxide-based particles (IOPs) visualized in vivo using magnetic resonance imaging (MRI). We discuss the types of IOPs available for such tracking, their advantages and limitations, approaches for labeling cells with IOPs, biological interactions and effects of IOPs at the molecular and cellular levels, and MRI-based and associated approaches for in vivo and histological visualization. We conclude with reviews of the literature on IOP-based cell tracking in cardiac and neurological disease, covering both preclinical and clinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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.

Similar content being viewed by others

Change history

References

  1. Uygur A, Lee RT (2016) Mechanisms of cardiac regeneration. Dev Cell 36:362–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Winner B, Winkler J (2015) Adult neurogenesis in neurodegenerative diseases. Cold Spring Harb Perspect Biol 7:a021287

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tuszynski MH, Wang Y, Graham L et al (2014) Neural stem cells in models of spinal cord injury. Exp Neurol 261:494–500

    Article  CAS  PubMed  Google Scholar 

  4. Rafatian G, Davis DR (2018) Concise review: heart-derived cell therapy 2.0: paracrine strategies to increase therapeutic repair of injured myocardium. Stem Cells 36:1794–1803

    Article  PubMed  Google Scholar 

  5. Aarntzen EH, Srinivas M, Walczak P et al (2012) In vivo tracking techniques for cellular regeneration, replacement, and redirection. J Nucl Med 53:1825–1828

    Article  CAS  PubMed  Google Scholar 

  6. Srivastava AK, Bulte JW (2014) Seeing stem cells at work in vivo. Stem Cell 10:127–144

    Article  Google Scholar 

  7. Cromer Berman SM, Walczak P, Bulte JW (2011) Tracking stem cells using magnetic nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3:343–355

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Contag CH, Bachmann MH (2002) Advances in in vivo bioluminescence imaging of gene expression. Annu Rev Biomed Eng 4:235–260

    Article  CAS  PubMed  Google Scholar 

  9. Helmchen F, Denk W (2005) Deep tissue two-photon microscopy. Nat Methods 2:932–940

    Article  CAS  PubMed  Google Scholar 

  10. Jacobs RE, Cherry SR (2001) Complementary emerging techniques: high-resolution PET and MRI. Curr Opin Neurobiol 11:621–629

    Article  CAS  PubMed  Google Scholar 

  11. de Kemp RA, Epstein FH, Catana C et al (2010) Small-animal molecular imaging methods. J Nucl Med 51 Suppl 1:18s–32s

    Article  PubMed  CAS  Google Scholar 

  12. Long CM, Bulte JW (2009) In vivo tracking of cellular therapeutics using magnetic resonance imaging. Expert Opin Biol Ther 9:293–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li SC, Tachiki LM, Luo J et al (2010) A biological global positioning system: considerations for tracking stem cell behaviors in the whole body. Stem Cell Rev 6:317–333

    Article  PubMed Central  Google Scholar 

  14. Hoehn M, Kustermann 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 USA 99:16267–16272

  15. Wen X, Wang Y, Zhang F et al (2014) In vivo monitoring of neural stem cells after transplantation in acute cerebral infarction with dual-modal MR imaging and optical imaging. Biomaterials 35:4627–4635

    Article  CAS  PubMed  Google Scholar 

  16. Modo M, Beech JS, Meade TJ et al (2009) A chronic 1 year assessment of MRI contrast agent-labelled neural stem cell transplants in stroke. Neuroimage 47(Suppl 2):T133–T142

    Article  PubMed  Google Scholar 

  17. Modo M, Mellodew K, Cash D et al (2004) Mapping transplanted stem cell migration after a stroke: a serial, in vivo magnetic resonance imaging study. Neuroimage 21:311–317

    Article  PubMed  Google Scholar 

  18. Lee JH, Huh YM, Jun YW et al (2007) Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging. Nat Med 13:95–99

    Article  CAS  PubMed  Google Scholar 

  19. Shen T, Weissleder R, Papisov M et al (1993) Monocrystalline iron oxide nanocompounds (MION): physicochemical properties. Magn Reson Med 29:599–604

    Article  CAS  PubMed  Google Scholar 

  20. 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 56:1001–1010

    Article  PubMed  Google Scholar 

  21. Shapiro EM, Sharer K, Skrtic S, Koretsky AP (2006) In vivo detection of single cells by MRI. Magn Reson Med 55:242–249

    Article  PubMed  Google Scholar 

  22. Shubayev VI, Pisanic TR 2nd, Jin S (2009) Magnetic nanoparticles for theragnostics. Adv Drug Deliv Rev 61:467–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Masserini (2013) Nanoparticles for brain drug delivery. ISRN Biochem 2013:238428

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Nkansah MK, Thakral D, Shapiro EM (2011) Magnetic poly(lactide-co-glycolide) and cellulose particles for MRI-based cell tracking. Magn Reson Med 65:1776–1785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shapiro EM (2015) Biodegradable, polymer encapsulated, metal oxide particles for MRI-based cell tracking. Magn Reson Med 73:376–389

    Article  CAS  PubMed  Google Scholar 

  26. De Cuyper M, Joniau M (1988) Magnetoliposomes. Formation and structural characterization. Eur Biophys J 15:311–319

    Article  PubMed  Google Scholar 

  27. Monnier CA BD, Rothen-Rutishauer B, Lattuada M, Petri-Fink A (2014) Magnetoliposomes: opportunities and challenges. Eur J Nanomed 6. doi https://doi.org/10.1515/ejnm-2014-0042.

  28. Barrow M, Taylor A, Murray P et al (2015) Design considerations for the synthesis of polymer coated iron oxide nanoparticles for stem cell labelling and tracking using MRI. Chem Soc Rev 44:6733–6748

    Article  CAS  PubMed  Google Scholar 

  29. Yeh TC, Zhang W, Ildstad ST, Ho C (1993) Intracellular labeling of T-cells with superparamagnetic contrast agents. Magn Reson Med 30:617–625

    Article  CAS  PubMed  Google Scholar 

  30. Yeh TC, Zhang W, Ildstad ST, Ho C (1995) In vivo dynamic MRI tracking of rat T-cells labeled with superparamagnetic iron-oxide particles. Magn Reson Med 33:200–208

    Article  CAS  PubMed  Google Scholar 

  31. Lojk J, Bregar VB, Rajh M et al (2015) Cell type-specific response to high intracellular loading of polyacrylic acid-coated magnetic nanoparticles. Int J Nanomedicine 10:1449–1462

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Josephson L, Tung CH, Moore A, Weissleder R (1999) High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. Bioconjug Chem 10:186–191

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Kraitchman DL, Heldman AW, Atalar E et al (2003) In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 107:2290–2293

    Article  PubMed  Google Scholar 

  35. 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 228:480–487

    Article  PubMed  Google Scholar 

  36. Arbab AS, Bashaw LA, Miller BR et al (2003) Intracytoplasmic tagging of cells with ferumoxides and transfection agent for cellular magnetic resonance imaging after cell transplantation: methods and techniques. Transplantation 76:1123–1130

    Article  CAS  PubMed  Google Scholar 

  37. Arbab AS, Yocum GT, Kalish H et al (2004) Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. Blood 104:1217–1223

    Article  CAS  PubMed  Google Scholar 

  38. Thu MS, Najbauer J, Kendall SE et al (2009) Iron labeling and pre-clinical MRI visualization of therapeutic human neural stem cells in a murine glioma model. PLoS One 4:e7218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Kustermann E, Himmelreich U, Kandal K et al (2008) Efficient stem cell labeling for MRI studies. Contrast Media Mol Imaging 3:27–37

    Article  CAS  PubMed  Google Scholar 

  40. Walczak P, Kedziorek DA, Gilad AA et al (2005) Instant MR labeling of stem cells using magnetoelectroporation. Magn Reson Med 54:769–774

    Article  CAS  PubMed  Google Scholar 

  41. Walczak P, Ruiz-Cabello J, Kedziorek DA et al (2006) Magnetoelectroporation: improved labeling of neural stem cells and leukocytes for cellular magnetic resonance imaging using a single FDA-approved agent. Nanomedicine 2:89–94

    Article  CAS  PubMed  Google Scholar 

  42. Qiu B, Xie D, Walczak P et al (2010) Magnetosonoporation: instant magnetic labeling of stem cells. Magn Reson Med 63:1437–1441

    Article  PubMed  Google Scholar 

  43. Xie D, Qiu B, Walczak P et al (2010) Optimization of magnetosonoporation for stem cell labeling. NMR Biomed 23:480–484

    Article  PubMed  Google Scholar 

  44. Bulte JW, Zhang S, van Gelderen P et al (1999) Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. Proc Natl Acad Sci U S A 96:15256–15261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 49:1006–1013

    Article  CAS  PubMed  Google Scholar 

  46. Shapiro EM, Medford-Davis LN, Fahmy TM et al (2007) Antibody-mediated cell labeling of peripheral T cells with micron-sized iron oxide particles (MPIOs) allows single cell detection by MRI. Contrast Media Mol Imaging 2:147–153

    Article  CAS  PubMed  Google Scholar 

  47. Hill JM, Dick AJ, Raman VK et al (2003) Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 108:1009–1014

    Article  PubMed  PubMed Central  Google Scholar 

  48. Arbab AS, Yocum GT, Rad AM 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  PubMed  Google Scholar 

  49. Boulland JL, Leung DS, Thuen M et al (2012) Evaluation of intracellular labeling with micron-sized particles of iron oxide (MPIOs) as a general tool for in vitro and in vivo tracking of human stem and progenitor cells. Cell Transplant 21:1743–1759

    Article  PubMed  Google Scholar 

  50. Detante O, Valable S, de Fraipont F et al (2012) Magnetic resonance imaging and fluorescence labeling of clinical-grade mesenchymal stem cells without impacting their phenotype: study in a rat model of stroke. Stem Cells Transl Med 1:333–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shen WB, Plachez C, Chan A et al (2013) Human neural progenitor cells retain viability, phenotype, proliferation, and lineage differentiation when labeled with a novel iron oxide nanoparticle, Molday ION Rhodamine B. Int J Nanomedicine 8:4593–4600

    PubMed  PubMed Central  Google Scholar 

  52. Kostura L, Kraitchman DL, Mackay AM et al (2004) Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis. NMR Biomed 17:513–517

    Article  PubMed  Google Scholar 

  53. Bulte JW, Kraitchman DL, Mackay AM, Pittenger MF (2004) Chondrogenic differentiation of mesenchymal stem cells is inhibited after magnetic labeling with ferumoxides. Blood 104:3410–3412 author reply 3412-3

    Article  CAS  PubMed  Google Scholar 

  54. Chen YC, Hsiao JK, Liu HM et al (2010) The inhibitory effect of superparamagnetic iron oxide nanoparticle (Ferucarbotran) on osteogenic differentiation and its signaling mechanism in human mesenchymal stem cells. Toxicol Appl Pharmacol 245:272–279

    Article  CAS  PubMed  Google Scholar 

  55. Nohroudi K, Arnhold S, Berhorn T et al (2010) In vivo MRI stem cell tracking requires balancing of detection limit and cell viability. Cell Transplant 19:431–441

    Article  CAS  PubMed  Google Scholar 

  56. Bulte JW, Douglas T, Witwer B et al (2001) Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 19:1141–1147

    Article  CAS  PubMed  Google Scholar 

  57. Cohen ME, Muja N, Fainstein N et al (2010) Conserved fate and function of ferumoxides-labeled neural precursor cells in vitro and in vivo. J Neurosci Res 88:936–944

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Guzman R, Uchida N, Bliss TM et al (2007) Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proc Natl Acad Sci U S A 104:10211–10216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Focke A, Schwarz S, Foerschler A et al (2008) Labeling of human neural precursor cells using ferromagnetic nanoparticles. Magn Reson Med 60:1321–1328

    Article  CAS  PubMed  Google Scholar 

  60. Ramos-Gomez M, Seiz EG, Martinez-Serrano A (2015) Optimization of the magnetic labeling of human neural stem cells and MRI visualization in the hemiparkinsonian rat brain. J Nanobiotechnol 13:20

    Article  CAS  Google Scholar 

  61. Goodfellow F, Simchick GA, Mortensen LJ et al (2016) Tracking and quantification of magnetically labeled stem cells using magnetic resonance imaging. Adv Funct Mater 26:3899–3915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Au KW, Liao SY, Lee YK et al (2009) Effects of iron oxide nanoparticles on cardiac differentiation of embryonic stem cells. Biochem Biophys Res Commun 379:898–903

    Article  CAS  PubMed  Google Scholar 

  63. Wang YX (2011) Superparamagnetic iron oxide based MRI contrast agents: current status of clinical application. Quant Imaging Med Surg 1:35–40

    PubMed  PubMed Central  Google Scholar 

  64. Tu C, Ng TS, Sohi HK et al (2011) Receptor-targeted iron oxide nanoparticles for molecular MR imaging of inflamed atherosclerotic plaques. Biomaterials 32:7209–7216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. McAteer MA, Schneider JE, Ali ZA et al (2008) Magnetic resonance imaging of endothelial adhesion molecules in mouse atherosclerosis using dual-targeted microparticles of iron oxide. Arterioscler Thromb Vasc Biol 28:77–83

    Article  CAS  PubMed  Google Scholar 

  66. Argibay B, Trekker J, Himmelreich U et al (2017) Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia. Sci Rep 7:40758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Saiyed ZM, Gandhi NH, Nair MP (2010) Magnetic nanoformulation of azidothymidine 5'-triphosphate for targeted delivery across the blood-brain barrier. Int J Nanomedicine 5:157–166

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Yuan ZY, Hu YL, Gao JQ (2015) Brain localization and neurotoxicity evaluation of polysorbate 80-modified chitosan nanoparticles in rats. PLoS One 10:e0134722

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Kong SD, Lee J, Ramachandran S et al (2012) Magnetic targeting of nanoparticles across the intact blood-brain barrier. J Control Release 164:49–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Thomsen LB, Linemann T, Pondman KM et al (2013) Uptake and transport of superparamagnetic iron oxide nanoparticles through human brain capillary endothelial cells. ACS Chem Neurosci 4:1352–1360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Busquets MA, Espargaro A, Sabate R, Estelrich J (2015) Magnetic nanoparticles cross the blood-brain barrier: when physics rises to a challenge. Nanomaterials 5:2231–2248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yarjanli Z, Ghaedi K, Esmaeili A et al (2017) Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. BMC Neurosci 18:51

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Cengelli F, Maysinger D, Tschudi-Monnet F et al (2006) Interaction of functionalized superparamagnetic iron oxide nanoparticles with brain structures. J Pharmacol Exp Ther 318:108–116

    Article  CAS  PubMed  Google Scholar 

  74. Imam SZ, Lantz-McPeak SM, Cuevas E et al (2015) Iron oxide nanoparticles induce dopaminergic damage: in vitro pathways and in vivo imaging reveals mechanism of neuronal damage. Mol Neurobiol 52:913–926

    Article  CAS  PubMed  Google Scholar 

  75. Desestret V, Brisset JC, Moucharrafie S et al (2009) Early-stage investigations of ultrasmall superparamagnetic iron oxide-induced signal change after permanent middle cerebral artery occlusion in mice. Stroke 40:1834–1841

    Article  PubMed  Google Scholar 

  76. Chang J, Jallouli Y, Kroubi M et al (2009) Characterization of endocytosis of transferrin-coated PLGA nanoparticles by the blood-brain barrier. Int J Pharm 379:285–292

    Article  CAS  PubMed  Google Scholar 

  77. Qiao R, Jia Q, Huwel S et al (2012) Receptor-mediated delivery of magnetic nanoparticles across the blood-brain barrier. ACS Nano 6:3304–3310

    Article  CAS  PubMed  Google Scholar 

  78. Wang B, Feng WY, Wang M et al (2007) Transport of intranasally instilled fine Fe2O3 particles into the brain: micro-distribution, chemical states, and histopathological observation. Biol Trace Elem Res 118:233–243

    Article  CAS  PubMed  Google Scholar 

  79. Wang B, Wang Q, Chen H et al (2016) Size-dependent translocation pattern, chemical and biological transformation of nano- and submicron-sized ferric oxide particles in the central nervous system. J Nanosci Nanotechnol 16:5553–5561

    Article  CAS  PubMed  Google Scholar 

  80. Suarez S, Almutairi A, Christman K (2015) Micro- and nanoparticles for treating cardiovascular disease. Biomater Sci 3:564–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chen J, Yang J, Liu R et al (2017) Dual-targeting theranostic system with mimicking apoptosis to promote myocardial infarction repair via modulation of macrophages. Theranostics 7:4149–4167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Terrovitis JV, Smith RR, Marban E (2010) Assessment and optimization of cell engraftment after transplantation into the heart. Circ Res 106:479–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhu J, Zhou L, XingWu F (2006) Tracking neural stem cells in patients with brain trauma. N Engl J Med 355:2376–2378

    Article  CAS  PubMed  Google Scholar 

  84. Afridi MJ, Ross A, Liu X et al (2017) Intelligent and automatic in vivo detection and quantification of transplanted cells in MRI. Magn Reson Med 78:1991–2002

    Article  PubMed  Google Scholar 

  85. Bulte JW, Walczak P, Janowski M et al (2015) Quantitative “hot spot” imaging of transplanted stem cells using superparamagnetic tracers and magnetic particle imaging (MPI). Tomography 1:91–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. van den Bos EJ, Baks T, Moelker AD et al (2006) Magnetic resonance imaging of haemorrhage within reperfused myocardial infarcts: possible interference with iron oxide-labelled cell tracking? Eur Heart J 27:1620–1626

    Article  PubMed  Google Scholar 

  87. 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(Suppl):I38–I45

    CAS  PubMed  Google Scholar 

  88. Zheng B, von See MP, Yu E et al (2016) Quantitative magnetic particle imaging monitors the transplantation, biodistribution, and clearance of stem cells in vivo. Theranostics 6:291–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hainfeld J, Slatkin D, Focella T, Smilowitz H (2006) Gold nanoparticles: a new x-ray contrast agent. Br J Radiol 79:248–253

    Article  CAS  PubMed  Google Scholar 

  90. Farini A, Villa C, Manescu A et al (2012) Novel insight into stem cell trafficking in dystrophic muscle. Int J Nanomed 7:3059–3067

    Google Scholar 

  91. Torrente Y, Gavina M, Belicchi M et al (2006) High resolution X-ray microtomography for three-dimensional visualization of human stem cell muclse homing. FEBS Letters 580:5759–5764

    Article  CAS  PubMed  Google Scholar 

  92. Albers J, Pacilé S, Markus M et al (2018) X-ray-based 3D virtual histology - adding the next dimension to histological analsysis. Mole Imaging Biol 20:732–741

    Article  CAS  Google Scholar 

  93. Kinney JH, Nichols MC (1992) X-ray tomographic microscopy (XTM) using synchrotron radiation. Ann Rev Mater Sci 22:121–152

    Article  CAS  Google Scholar 

  94. Withers PJ (2007) X.ray nanotomography. Materials Today 10:26–34

    Article  CAS  Google Scholar 

  95. Marinescu M, Langer M, Durand A et al (2013) Synchrotron radiation x-ray phase microcomputed tomography as a new method to detect iron oxide nanoparticles in the brain. Mol Imaging Biol 15:552–559

    Article  CAS  PubMed  Google Scholar 

  96. Scharlach C, Muller L, Wagner S et al (2016) LA-ICP-MS allows quantitative microscopy of europium-doped iron oxide nanoparticles and is a possible alternative to ambiguous prussian blue iron staining. J Biomed Nanotechnol 12:1001–1010

    Article  CAS  PubMed  Google Scholar 

  97. Sumner JP, Conroy R, Shapiro EM et al (2007) Delivery of fluorescent probes using iron oxide particles as carriers enables in-vivo labeling of migrating neural precursors for magnetic resonance imaging and optical imaging. J Biomed Opt 12:051504

    Article  PubMed  CAS  Google Scholar 

  98. Shen TT, Bogdanov A Jr, Bogdanova A, Pet al. (1996) Magnetically labeled secretin retains receptor affinity to pancreas acinar cells. Bioconjug Chem 7:311–316

    Article  CAS  PubMed  Google Scholar 

  99. De Palma R, Trekker J, Peeters S et al (2007) Surface modification of gamma-Fe2O3@SiO2 magnetic nanoparticles for the controlled interaction with biomolecules. J Nanosci Nanotechnol 7:4626–4641

    Article  PubMed  Google Scholar 

  100. Amstad E, Zurcher S, Mashaghi A et al (2009) Surface functionalization of single superparamagnetic iron oxide nanoparticles for targeted magnetic resonance imaging. Small 5:1334–1342

    Article  CAS  PubMed  Google Scholar 

  101. Wei H, Insin N, Lee J et al (2012) Compact zwitterion-coated iron oxide nanoparticles for biological applications. Nano Lett 12:22–25

    Article  CAS  PubMed  Google Scholar 

  102. Yang T, Sun S, Ma M et al (2015) Optimizing immobilization of avidin on surface-modified magnetic nanoparticles: characterization and application of protein-immobilized nanoparticles. Bioprocess Biosyst Eng 38:2023–2034

    Article  CAS  PubMed  Google Scholar 

  103. Odintsov B, Chun JL, Berry SE (2013) Whole body MRI and fluorescent microscopy for detection of stem cells labeled with superparamagnetic iron oxide (SPIO) nanoparticles and DiI following intramuscular and systemic delivery. Methods Mol Biol 1052:177–193

    Article  CAS  PubMed  Google Scholar 

  104. Markides H, Kehoe O, Morris RH, El Haj AJ (2013) Whole body tracking of superparamagnetic iron oxide nanoparticle-labelled cells--a rheumatoid arthritis mouse model. Stem Cell Res Ther 4:126

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Rossini A, Frati C, Lagrasta C et al (2011) Human cardiac and bone marrow stromal cells exhibit distinctive properties related to their origin. Cardiovasc Res 89:650–660

    Article  CAS  PubMed  Google Scholar 

  106. Glover JC (1995) Retrograde and anterograde axonal tracing with fluorescent dextrans in the embryonic nervous system. Neurosci Protocols 30:1–13

    Google Scholar 

  107. Glover JC (2014) Conjugated dextran amines as intracellular tracers for visualizing and manipulating neurons. In: FG P (ed) Dextran: chemical structure, applications and potential side effects. Recent trends in biotechnology. Nova Publishers, Hauppauge, pp 157–174

    Google Scholar 

  108. Aggarwal P, Hall JB, McLeland CB et al (2009) Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliv Rev 61:428–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Treuel L, Docter D, Maskos M, Stauber RH (2015) Protein corona - from molecular adsorption to physiological complexity. Beilstein J Nanotechnol 6:857–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Safi M, Courtois J, Seigneuret M et al (2011) The effects of aggregation and protein corona on the cellular internalization of iron oxide nanoparticles. Biomaterials 32:9353–9363

    Article  CAS  PubMed  Google Scholar 

  111. Pavlin M, Bregar VB (2012) Stability of nanoparticle suspensions in different biologically relevant media. Dig J Nanomater Bios 7:1389–1400

    Google Scholar 

  112. Tenzer S, Docter D, Kuharev J et al (2013) Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nat Nanotechnol 8:772–781

    Article  CAS  PubMed  Google Scholar 

  113. Strojan K, Leonardi A, Bregar VB et al (2017) Dispersion of nanoparticles in different media importantly determines the composition of their protein corona. PLoS One 12:e0169552

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Chen F, Wang G, Griffin JI et al (2017) Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo. Nat Nanotechnol 12:387–393

    Article  CAS  PubMed  Google Scholar 

  115. Lundqvist M, Stigler J, Elia G et al (2008) Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci U S A 105:14265–14270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Deng ZJ, Liang M, Monteiro M et al (2011) Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammation. Nat Nanotechnol 6:39–44

    Article  CAS  PubMed  Google Scholar 

  117. Iversen T-G, Skotland T, Sandvig K (2011) Endocytosis and intracellular transport of nanoparticles: present knowledge and need for future studies. NanoToday 6:176–185

    Article  CAS  Google Scholar 

  118. Kuhn DA, Vanhecke D, Michen B et al (2014) Different endocytotic uptake mechanisms for nanoparticles in epithelial cells and macrophages. Beilstein J Nanotechnol 5:1625–1636

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Akinc A, Battaglia G (2013) Exploiting endocytosis for nanomedicines. Cold Spring Harb Perspect Biol 5:a016980

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Ali LM, Pinol R, Villa-Bellosta R et al (2015) Cell compatibility of a maghemite/polymer biomedical nanoplatform. Toxicol In Vitro 29:962–975

    Article  CAS  PubMed  Google Scholar 

  121. Petters C, Bulcke F, Thiel K et al (2014) Uptake of fluorescent iron oxide nanoparticles by oligodendroglial OLN-93 cells. Neurochem Res 39:372–383

    Article  CAS  PubMed  Google Scholar 

  122. Petters C, Dringen R (2015) Accumulation of iron oxide nanoparticles by cultured primary neurons. Neurochem Int 81:1–9

    Article  CAS  PubMed  Google Scholar 

  123. Bareford LM, Swaan PW (2007) Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev 59:748–758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Freeman SA, Grinstein S (2014) Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol Rev 262:193–215

    Article  CAS  PubMed  Google Scholar 

  125. Liu D, Wu W, Ling J et al (2011) Effective PEGylation of iron oxide nanoparticles for high performance in vivo cancer imaging. Adv Funct Mater 21:1498–1504

    Article  CAS  Google Scholar 

  126. Ni F, Jiang L, Yang R et al (2012) Effects of PEG length and iron oxide nanoparticles size on reduced protein adsorption and non-specific uptake by macrophage cells. J Nanosci Nanotechnol 12:2094–2100

    Article  CAS  PubMed  Google Scholar 

  127. Bobo D, Robinson KJ, Islam J et al (2016) Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res 33:2373–2387

    Article  CAS  PubMed  Google Scholar 

  128. Moghimi SM, Andersen AJ, Hashemi SH et al (2010) Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: the challenges ahead. J Control Release 146:175–181

    Article  CAS  PubMed  Google Scholar 

  129. Szebeni J, Baranyi L, Savay S et al (2006) Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function. Am J Physiol Heart Circ Physiol 290:H1050–H1058

    Article  CAS  PubMed  Google Scholar 

  130. Andersen AJ, Windschiegl B, Ilbasmis-Tamer S et al (2013) Complement activation by PEG-functionalized multi-walled carbon nanotubes is independent of PEG molecular mass and surface density. Nanomedicine 9:469–473

    Article  CAS  PubMed  Google Scholar 

  131. Banda NK, Mehta G, Chao Y et al (2014) Mechanisms of complement activation by dextran-coated superparamagnetic iron oxide (SPIO) nanoworms in mouse versus human serum. Part Fibre Toxicol 11:64

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Wang G, Chen F, Banda NK et al (2016) Activation of human complement system by dextran-coated iron oxide nanoparticles is not affected by dextran/Fe ratio, hydroxyl modifications, and crosslinking. Front Immunol 7:418

    PubMed  PubMed Central  Google Scholar 

  133. Wolf-Grosse S, Rokstad AM, Ali S et al (2017) Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model. Int J Nanomed 12:3927–3940

    Article  CAS  Google Scholar 

  134. Cengelli F, Voinesco F, Juillerat-Jeanneret L (2010) Interaction of cationic ultrasmall superparamagnetic iron oxide nanoparticles with human melanoma cells. Nanomedicine 5:1075–1087

    Article  CAS  PubMed  Google Scholar 

  135. Wu X, Tan Y, Mao H, Zhang M (2010) Toxic effects of iron oxide nanoparticles on human umbilical vein endothelial cells. Int J Nanomedicine 5:385–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Geppert M, Hohnholt MC, Thiel K et al (2011) Uptake of dimercaptosuccinate-coated magnetic iron oxide nanoparticles by cultured brain astrocytes. Nanotechnology 22:145101

    Article  PubMed  CAS  Google Scholar 

  137. Kumar M, Singh G, Arora V et al (2012) Cellular interaction of folic acid conjugated superparamagnetic iron oxide nanoparticles and its use as contrast agent for targeted magnetic imaging of tumor cells. Int J Nanomed 7:3503–3516

    CAS  Google Scholar 

  138. Zhang X, Zhang H, Liang X et al (2016) Iron oxide nanoparticles induce autophagosome accumulation through multiple mechanisms: lysosome impairment, mitochondrial damage, and ER stress. Mol Pharm 13:2578–2587

    Article  CAS  PubMed  Google Scholar 

  139. Bregar VB, Lojk J, Sustar V et al (2013) Visualization of internalization of functionalized cobalt ferrite nanoparticles and their intracellular fate. Int J Nanomedicine 8:919–931

    PubMed  PubMed Central  Google Scholar 

  140. Ndong C, Tate JA, Kett WC et al (2015) Tumor cell targeting by iron oxide nanoparticles is dominated by different factors in vitro versus in vivo. PLoS One 10:e0115636

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Arbab AS, Wilson LB, Ashari P et al (2005) A model of lysosomal metabolism of dextran coated superparamagnetic iron oxide (SPIO) nanoparticles: implications for cellular magnetic resonance imaging. NMR Biomed 18:383–389

    Article  CAS  PubMed  Google Scholar 

  142. Levy M, Lagarde F, Maraloiu VA et al (2010) Degradability of superparamagnetic nanoparticles in a model of intracellular environment: follow-up of magnetic, structural and chemical properties. Nanotechnology 21:395103

    Article  PubMed  CAS  Google Scholar 

  143. Soenen SJ, Himmelreich U, Nuytten N et al (2010) Intracellular nanoparticle coating stability determines nanoparticle diagnostics efficacy and cell functionality. Small 6:2136–2145

    Article  CAS  PubMed  Google Scholar 

  144. Malvindi MA, De Matteis V, Galeone A et al (2014) Toxicity assessment of silica coated iron oxide nanoparticles and biocompatibility improvement by surface engineering. PLoS One 9:e85835

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Sabella S, Carney RP, Brunetti V et al (2014) A general mechanism for intracellular toxicity of metal-containing nanoparticles. Nanoscale 6:7052–7061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Gutierrez L, Romero S, da Silva GB et al (2015) Degradation of magnetic nanoparticles mimicking lysosomal conditions followed by AC susceptibility. Biomed Tech 60:417–425

    Article  CAS  Google Scholar 

  147. Volatron J, Carn F, Kolosnjaj-Tabi J, et al. (2017) Ferritin protein regulates the degradation of iron oxide nanoparticles. Small 13. doi https://doi.org/10.1002/smll.201602030

  148. Weissleder R, Stark DD, Engelstad BL et al (1989) Superparamagnetic iron oxide: pharmacokinetics and toxicity. AJR Am J Roentgenol 152:167–173

    Article  CAS  PubMed  Google Scholar 

  149. Pouliquen D, Le Jeune JJ, Perdrisot R et al (1991) Iron oxide nanoparticles for use as an MRI contrast agent: pharmacokinetics and metabolism. Magn Reson Imaging 9:275–283

    Article  CAS  PubMed  Google Scholar 

  150. Sakhtianchi R, Minchin RF, Lee KB et al (2013) Exocytosis of nanoparticles from cells: role in cellular retention and toxicity. Adv Colloid Interface Sci 201-202:18–29

    Article  CAS  PubMed  Google Scholar 

  151. Parton RG, del Pozo MA (2013) Caveolae as plasma membrane sensors, protectors and organizers. Nat Rev Mol Cell Biol 14:98–112

    Article  CAS  PubMed  Google Scholar 

  152. Kafshgari MH, Harding FJ, Voelcker NH (2015) Insights into cellular uptake of nanoparticles. Curr Drug Deliv 12:63–77

    Article  CAS  PubMed  Google Scholar 

  153. Wu H, Yin JJ, Wamer WG et al (2014) Reactive oxygen species-related activities of nano-iron metal and nano-iron oxides. J Food Drug Anal 22:86–94

    Article  CAS  PubMed  Google Scholar 

  154. Hohnholt MC, Dringen R (2011) Iron-dependent formation of reactive oxygen species and glutathione depletion after accumulation of magnetic iron oxide nanoparticles by oligodendroglial cells. J Nanopart Res 13:6761–6774

    Article  CAS  Google Scholar 

  155. Lunov O, Syrovets T, Rocker C et al (2010) Lysosomal degradation of the carboxydextran shell of coated superparamagnetic iron oxide nanoparticles and the fate of professional phagocytes. Biomaterials 31:9015–9022

    Article  CAS  PubMed  Google Scholar 

  156. Laskar A, Ghosh M, Khattak SI, Li W, Yuan XM (2012) Degradation of superparamagnetic iron oxide nanoparticle-induced ferritin by lysosomal cathepsins and related immune response. Nanomedicine 7:705–717

    Article  CAS  PubMed  Google Scholar 

  157. Munoz Y, Carrasco CM, Campos JD, et al. (2016) Parkinson’s disease: the mitochondria-iron link. Parkinsons Dis 2016. doi: https://doi.org/10.1155/2016/7049108

  158. Nunez MT, Urrutia P, Mena N et al (2012) Iron toxicity in neurodegeneration. Biometals 25:761–776

    Article  CAS  PubMed  Google Scholar 

  159. Park EJ, Choi DH, Kim Y et al (2014) Magnetic iron oxide nanoparticles induce autophagy preceding apoptosis through mitochondrial damage and ER stress in RAW264.7 cells. Toxicol In Vitro 28:1402–1412

    Article  CAS  PubMed  Google Scholar 

  160. Soenen SJ, Nuytten N, De Meyer SF et al (2010) High intracellular iron oxide nanoparticle concentrations affect cellular cytoskeleton and focal adhesion kinase-mediated signaling. Small 6:832–842

    Article  CAS  PubMed  Google Scholar 

  161. Soenen SJ, Himmelreich U, Nuytten N, De Cuyper M (2011) Cytotoxic effects of iron oxide nanoparticles and implications for safety in cell labelling. Biomaterials 32:195–205

    Article  CAS  PubMed  Google Scholar 

  162. Diana V, Bossolasco P, Moscatelli D et al (2013) Dose dependent side effect of superparamagnetic iron oxide nanoparticle labeling on cell motility in two fetal stem cell populations. PLoS One 8:e78435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Pongrac IM, Pavicic I, Milic M et al (2016) Oxidative stress response in neural stem cells exposed to different superparamagnetic iron oxide nanoparticles. Int J Nanomed 11:1701–1715

    CAS  Google Scholar 

  164. Kehrer JP (2000) The Haber-Weiss reaction and mechanisms of toxicity. Toxicology 149:43–50

    Article  CAS  PubMed  Google Scholar 

  165. Geppert M, Hohnholt MC, Nurnberger S, Dringen R (2012) Ferritin up-regulation and transient ROS production in cultured brain astrocytes after loading with iron oxide nanoparticles. Acta Biomater 8:3832–3839

    Article  CAS  PubMed  Google Scholar 

  166. Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7:65–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Urrutia PJ, Mena NP, Nunez MT (2014) The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Front Pharmacol 5:38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Liu G, Men P, Perry G, Smith MA (2010) Nanoparticle and iron chelators as a potential novel Alzheimer therapy. Methods Mol Biol 610:123–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Mochizuki H, Yasuda T (2012) Iron accumulation in Parkinson’s disease. J Neural Transm 119:1511–1514

    Article  CAS  PubMed  Google Scholar 

  170. Ayton S, Lei P (2014) Nigral iron elevation is an invariable feature of Parkinson’s disease and is a sufficient cause of neurodegeneration. Biomed Res Int 2014:581256

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Eschenhagen T, Bolli R, Braun T et al (2017) Cardiomyocyte regeneration: a consensus statement. Circulation 136:680–686

    Article  PubMed  PubMed Central  Google Scholar 

  172. Gyöngyösi M, Haller PM, Blake DJ, Martin Rendon E (2018) meta-analysis of cell therapy studies in heart failure and acute myocardial infarction. Circ Res 123:301–308

    Article  PubMed  CAS  Google Scholar 

  173. Tateishi-Yuyama E, Matsubara H, Murohara T et al (2002) Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360:427–435

    Article  PubMed  Google Scholar 

  174. Higashi Y, Kimura M, Hara K et al (2004) Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia. Circulation 109:1215–1218

    Article  PubMed  Google Scholar 

  175. Huang PP, Li SZ, Han MZ et al (2004) Autologous transplantation of peripheral blood stem cells as an effective therapeutic approach for severe arteriosclerosis obliterans of lower extremities. Thromb Haemost 91:606–609

    Article  CAS  PubMed  Google Scholar 

  176. Emani SM, Del Nido PJ (2018) Cell-based therapy with cardiosphere-derived cardiocytes: a new hope for pediatric patients with single ventricle congenital heart disease? Circ Res 122:916–917

    Article  CAS  PubMed  Google Scholar 

  177. Gerber TC, Carr JJ, Arai AE et al (2009) Ionizing radiation in cardiac imaging: a science advisory from the American Heart Association Committee on Cardiac Imaging of the Council on Clinical Cardiology and Committee on Cardiovascular Imaging and Intervention of the Council on Cardiovascular Radiology and Intervention. Circulation 119:1056–1065

    Article  PubMed  Google Scholar 

  178. Luo L, Nishi K, Urata Y et al (2017) Ionizing radiation impairs endogenous regeneration of infarcted heart: an in vivo 18F-FDG PET/CT and 99mTc-tetrofosmin SPECT/CT study in mice. Radiat Res 187:89–97

    Article  CAS  PubMed  Google Scholar 

  179. Himes N, Min JY, Lee R et al (2004) In vivo MRI of embryonic stem cells in a mouse model of myocardial infarction. Magn Reson Med 52:1214–1219

    Article  PubMed  Google Scholar 

  180. Arai T, Kofidis T, Bulte JW et al (2006) Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 t. Magn Reson Med 55:203–209

    Article  PubMed  Google Scholar 

  181. Mani V, Adler E, Briley-Saebo KC et al (2008) Serial in vivo positive contrast MRI of iron oxide-labeled embryonic stem cell-derived cardiac precursor cells in a mouse model of myocardial infarction. Magn Reson Med 60:73–81

    Article  PubMed  Google Scholar 

  182. Amado LC, Saliaris AP, Schuleri KH et al (2005) Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci USA 102:11474–11479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  184. Richards JM, Shaw CA, Lang NN et al (2012) In vivo mononuclear cell tracking using superparamagnetic particles of iron oxide: feasibility and safety in humans. Circ Cardiovasc Imaging 5:509–517

    Article  PubMed  Google Scholar 

  185. Lindvall O, Kokaia Z (2006) Stem cells for the treatment of neurological disorders. Nature 441:1094–1096

    Article  CAS  PubMed  Google Scholar 

  186. Naumova AV, Modo M, Moore A et al (2014) Clinical imaging in regenerative medicine. Nat Biotechnol 32:804–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Hoehn M, Himmelreich U, Kruttwig K, Wiedermann D (2008) Molecular and cellular MR imaging: potentials and challenges for neurological applications. J Magn Reson Imaging 27:941–954

    Article  PubMed  Google Scholar 

  188. Neri M, Maderna C, Cavazzin C et al (2008) Efficient in vitro labeling of human neural precursor cells with superparamagnetic iron oxide particles: relevance for in vivo cell tracking. Stem Cells 26:505–516

    Article  CAS  PubMed  Google Scholar 

  189. Crabbe A, Vandeputte C, Dresselaers T et al (2010) Effects of MRI contrast agents on the stem cell phenotype. Cell Transplant 19:919–936

    Article  PubMed  Google Scholar 

  190. Kallur T, Farr TD, Bohm-Sturm P et al (2011) Spatio-temporal dynamics, differentiation and viability of human neural stem cells after implantation into neonatal rat brain. Eur J Neurosci 34:382–393

    Article  PubMed  Google Scholar 

  191. Cromer Berman SM, Kshitiz, Wang CJ et al (2013) Cell motility of neural stem cells is reduced after SPIO-labeling, which is mitigated after exocytosis. Magn Reson Med 69:255–262

    Article  CAS  PubMed  Google Scholar 

  192. Cianciaruso C, Pagani A, Martelli C et al (2014) Cellular magnetic resonance with iron oxide nanoparticles: long-term persistence of SPIO signal in the CNS after transplanted cell death. Nanomedicine 9:1457–1474

    Article  CAS  PubMed  Google Scholar 

  193. von der Haar K, Lavrentieva A, Stahl F et al (2015) Lost signature: progress and failures in in vivo tracking of implanted stem cells. Appl Microbiol Biotechnol 99:9907–9922

    Article  PubMed  CAS  Google Scholar 

  194. Ben-Hur T, van Heeswijk RB, Einstein O et al (2007) Serial in vivo MR tracking of magnetically labeled neural spheres transplanted in chronic EAE mice. Magn Reson Med 57:164–171

    Article  PubMed  Google Scholar 

  195. Jendelova P, Herynek V, DeCroos J et al (2003) Imaging the fate of implanted bone marrow stromal cells labeled with superparamagnetic nanoparticles. Magn Reson Med 50:767–776

    Article  CAS  PubMed  Google Scholar 

  196. Zhang Z, Jiang Q, Jiang F et al (2004) In vivo magnetic resonance imaging tracks adult neural progenitor cell targeting of brain tumor. Neuroimage 23:281–287

    Article  CAS  PubMed  Google Scholar 

  197. Jones J, Estirado A, Redondo C et al (2015) Mesenchymal stem cells improve motor functions and decrease neurodegeneration in ataxic mice. Mol Ther 23:130–138

    Article  CAS  PubMed  Google Scholar 

  198. Andres RH, Horie N, Slikker W et al (2011) Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain 134:1777–1789

    Article  PubMed  PubMed Central  Google Scholar 

  199. Berman SC, Galpoththawela C, Gilad AA et al (2011) Long-term MR cell tracking of neural stem cells grafted in immunocompetent versus immunodeficient mice reveals distinct differences in contrast between live and dead cells. Magn Reson Med 65:564–574

    Article  PubMed  Google Scholar 

  200. Frank JA, Kalish H, Jordan EK et al (2007) Color transformation and fluorescence of Prussian blue-positive cells: implications for histologic verification of cells labeled with superparamagnetic iron oxide nanoparticles. Mol Imaging 6:212–218

    Article  CAS  PubMed  Google Scholar 

  201. Jirakova K, Seneklova M, Jirak D et al (2016) The effect of magnetic nanoparticles on neuronal differentiation of induced pluripotent stem cell-derived neural precursors. Int J Nanomed 11:6267–6281

    Article  CAS  Google Scholar 

  202. Lu LJ, Wang Y, Cao MH et al (2017) A novel polymeric micelle used for in vivo MR imaging tracking of neural stem cells in acute ischemic stroke. Rsc Advances 7:15041–15052

    Article  CAS  Google Scholar 

  203. Aswendt M, Henn N, Michalk S et al (2015) Novel bimodal iron oxide particles for efficient tracking of human neural stem cells in vivo. Nanomedicine 10:2499–2512

    Article  CAS  PubMed  Google Scholar 

  204. Ramos-Gomez M, Martinez-Serrano A (2016) Tracking of iron-labeled human neural stem cells by magnetic resonance imaging in cell replacement therapy for Parkinson’s disease. Neural Regen Res 11:49–52

    Article  PubMed  PubMed Central  Google Scholar 

  205. Himmelreich U, Weber R, Ramos-Cabrer P et al (2005) Improved stem cell MR detectability in animal models by modification of the inhalation gas. Mol Imaging 4:104–109

    Article  PubMed  Google Scholar 

  206. Cupaioli FA, Zucca FA, Boraschi D, Zecca L (2014) Engineered nanoparticles. How brain friendly is this new guest? Prog Neurobiol 119-120:20–38

    Article  CAS  PubMed  Google Scholar 

  207. Zheng B, Vazin T, Goodwill PW et al (2015) Magnetic particle imaging tracks the long-term fate of in vivo neural cell implants with high image contrast. Sci Rep 5:14055

    Article  PubMed  PubMed Central  Google Scholar 

  208. Adamczak J, Aswendt M, Kreutzer C et al (2017) Neurogenesis upregulation on the healthy hemisphere after stroke enhances compensation for age-dependent decrease of basal neurogenesis. Neurobiol Dis 99:47–57

    Article  CAS  PubMed  Google Scholar 

  209. Adamczak J, Hoehn M (2015) Poststroke angiogenesis, con: dark side of angiogenesis. Stroke 46:e103–e104

    Article  PubMed  Google Scholar 

  210. Liu Z, Li Y, Zhang X et al (2008) Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment. Stroke 39:2571–2577

    Article  PubMed  PubMed Central  Google Scholar 

  211. Ramos-Cabrer P, Hoehn M (2012) MRI stem cell tracking for therapy in experimental cerebral ischemia. Transl Stroke Res 3:22–35

    Article  PubMed  Google Scholar 

  212. Modo M, Hoehn M, Bulte JW (2005) Cellular MR imaging. Mol Imaging 4:143–164

    Article  PubMed  Google Scholar 

  213. 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 25:2583–2592

    Article  PubMed  Google Scholar 

  214. Muja N, Bulte JW (2009) Magnetic resonance imaging of cells in experimental disease models. Prog Nucl Magn Reson Spectrosc 55:61–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Chaumeil MM, Gini B, Yang H et al (2012) Longitudinal evaluation of MPIO-labeled stem cell biodistribution in glioblastoma using high resolution and contrast-enhanced MR imaging at 14.1 tesla. Neuro Oncol 14:1050–1061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Elvira G, Garcia I, Benito M et al (2012) Live imaging of mouse endogenous neural progenitors migrating in response to an induced tumor. PLoS One 7:e44466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Karussis D, Karageorgiou C, Vaknin-Dembinsky A et al (2010) Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 67:1187–1194

    Article  PubMed  PubMed Central  Google Scholar 

  218. George PM, Steinberg GK (2015) Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron 87:297–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Steinberg GK, Kondziolka D, Wechsler LR et al (2016) Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke 47:1817–1824

    Article  PubMed  PubMed Central  Google Scholar 

  220. Janowski M, Walczak P, Kropiwnicki T et al (2014) Long-term MRI cell tracking after intraventricular delivery in a patient with global cerebral ischemia and prospects for magnetic navigation of stem cells within the CSF. PLoS One 9:e97631

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. 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 16:461–466

    Article  PubMed  Google Scholar 

  222. Jin R, Lin B, Li D, Ai H (2014) Superparamagnetic iron oxide nanoparticles for MR imaging and therapy: design considerations and clinical applications. Curr Opin Pharmacol 18:18–27

    Article  CAS  PubMed  Google Scholar 

  223. 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 101:10901–10906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

All of the authors are members of the COST action 16122, Biomaterials and advanced physical techniques for regenerative cardiology and neurology (BIONECA), which has supported seminars and workshops that have served as the springboard for composing this review.

Funding

JCG and JLB are supported by the Norwegian Research Council (grants 230000, 189374, 229654) and the Southeastern Norway Health Authority (grants 2011035, 2015045, 2015102, 2014119). MP and JL are supported by ARRS grants J7-7424, Z4-8229 and P1-0055. DM is supported by the Croatian Science Foundation (IP-2016-06-9451) and co-financed by the European Union through the European Regional Development Fund, Operational Programme Competitiveness and Cohesion, grant agreement no. KK.01.1.1.01.0007, CoRE – Neuro.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to Joel C. Glover.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article was updated to correct numerous mismatched references.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Glover, J.C., Aswendt, M., Boulland, JL. et al. In vivo Cell Tracking Using Non-invasive Imaging of Iron Oxide-Based Particles with Particular Relevance for Stem Cell-Based Treatments of Neurological and Cardiac Disease. Mol Imaging Biol 22, 1469–1488 (2020). https://doi.org/10.1007/s11307-019-01440-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-019-01440-4

Key words

Navigation