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WIREs Nanomed Nanobiotechnol
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Tracking stem cells using magnetic nanoparticles

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Abstract Stem cell therapies offer great promise for many diseases, especially those without current effective treatments. It is believed that noninvasive imaging techniques, which offer the ability to track the status of cells after transplantation, will expedite progress in this field and help to achieve maximized therapeutic effect. Today's biomedical imaging technology allows for real‐time, noninvasive monitoring of grafted stem cells including their biodistribution, migration, survival, and differentiation, with magnetic resonance imaging (MRI) of nanoparticle‐labeled cells being one of the most commonly used techniques. Among the advantages of MR cell tracking are its high spatial resolution, no exposure to ionizing radiation, and clinical applicability. In order to track cells by MRI, the cells need to be labeled with magnetic nanoparticles, for which many types exist. There are several cellular labeling techniques available, including simple incubation, use of transfection agents, magnetoelectroporation, and magnetosonoporation. In this overview article, we will review the use of different magnetic nanoparticles and discuss how these particles can be used to track the distribution of transplanted cells in different organ systems. Caveats and limitations inherent to the tracking of nanoparticle‐labeled stem cells are also discussed. WIREs Nanomed Nanobiotechnol 2011 3 343–355 DOI: 10.1002/wnan.140 This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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Schematic structure of a representative superparamagnetic iron oxide (SPIO) nanoparticle that is composed of an iron oxide core, dextran coating, and rhodamine as fluorescent marker.

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Serial optical bioluminescence imaging and magnetic resonance imaging (MRI) of H9c2 cells after transplantation. Optical bioluminescence imaging of a representative rat intramyocardially injected with 2 × 106 Fluc‐labeled cells (top panel, right) shows a robust distinct heart signal on day 1 (red arrow), compared to no discernable signal in a representative control rat having received non‐labeled cells (top panel, left). The signal increases slightly on day 3 but decreases rapidly to near‐background levels by day 6. MRI of a representative rat injected with 2 × 106 Feridex‐labeled cells (bottom panel, right) shows a large hypointense signal (red arrow) in the anterolateral wall of myocardium when viewed in short axis. The size of the signal decreases slightly over time, and the signal persists for at least 80 days post cell injection, even though the cells have died by day 6. No corresponding signal is observed on the short‐axis image of a representative control rat having received non‐labeled cells (bottom panel, left). A, P, R, and L indicate anterior, posterior, right, and left anatomical orientations, respectively. (Reprinted with permission from Ref 81. Copyright 2008 Academy of Molecular Imaging)

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MRI scans from a patient who received neural stem cells labeled with Feridex. The scan obtained before implantation of the labeled neural stem cells (a) did not show a pronounced hypointense signal around the lesion (asterisk) in the left temporal lobe, whereas circular areas of hypointense signal were visible at the injection sites 1 day after implantation (b). Four hypointense signals (black arrows) were observed at injection sites around the lesion on day 1 (c), day 7 (d), day 14 (e), and day 21 (f). On day 7 (d), dark signals (white arrow) posterior to the lesion were observed, a finding that is consistent with the presence of the labeled cells. By day 14 (e), the hypointense signals at the injection sites had faded, and another dark signal (white arrowhead) had appeared and spread along the border of the damaged brain tissue. By day 21 (f), the dark signal had thickened and extended further along the lesion (white arrow). (Reprinted with permission from Ref 69. Copyright 2006 Massachusetts Medical Society)

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Serial in vivo magnetic resonance imaging (MRI) tracking of intracerebroventricular (ICV)‐transplanted neurospheres in experimental autoimmune encephalomyelitis (EAE). Feridex‐labeled neurospheres were transplanted into the right ventricle of EAE mice (black arrow). At day 1 after ICV transplantation (a), cells featuring hypointense (black) signals are found exclusively within the cerebral ventricles and are absent within the corpus callosum (white arrow). At 4 (b) and 7 (c) days after ICV transplantation, some cells had migrated into the corpus callosum (white arrow). Ex vivo MRI at day 22 posttransplantation confirmed this pattern of migration (d). (Reprinted with permission from Ref 64. Copyright 2009 John Wiley & Sons, Inc)

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Serial in vivo magnetic resonance (MR) tracking of Endorem‐labeled MSCs (25 µg/mL iron and 0.375 µg/mL PLL). (a) Injection of 2 × 106 SPIO‐labeled MSCs 7 days after left coronary artery ligation creates a wide intramural area of hypointensity (arrows) at the anterior lateral ventricle (LV) wall. Positive signals are still visible after 28 days. (b) Similar magnetic signals (arrows) were produced by labeled cells injected to normal hearts. (c) Injection of unlabeled MSCs did not alter the magnetic signal of the myocardium. (Reprinted with permission from Ref 56. Copyright 2007 American Heart Association, Inc)

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Prussian blue staining of mesenchymal stem cells (MSCs) labeled with Feridex at 25 µg of iron per milliliter of culture medium for 2 h (40× magnification): Feridex only (a); Feridex‐PLL (1200 ng/mL PLL) (b); Feridex‐Superfect (2400 ng/mL Superfect) (c); Feridex‐PLUS/lipofectamine (1:1250/1:2500 dilution from stock solution, Invitrogen, Carlsbad, CA) (d). Diamino‐benzidine‐enhanced Prussian blue staining of C17.2 mouse neural stem cells labeled with Feridex (2 mg/mL) with (e) and without magnetoelectroporation (f). (a–d, Reprinted with permission from Ref 38. Copyright 2003 Radiological Society of North America. E–F, Reprinted with permission from Ref 43. Copyright 2005 John Wiley & Sons, Inc)

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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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