Magnetic Resonance-Based Tracking and Quantification of Intravenously Injected Neural Stem Cell Accumulation in the Brains of Mice with Experimental Multiple Sclerosis

Authors

  • Letterio S. Politi,

    1. Neuroradiology Unit, San Raffaele Scientific Institute, Milan, Italy
    2. Centro Eccellenza Risonanza Magnetica ad Alto Campo, San Raffaele Scientific Institute, Milan, Italy
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  • Marco Bacigaluppi,

    1. Neuroimmunology Unit, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan, Italy
    2. Institute of Experimental Neurology (InSpe), San Raffaele Scientific Institute, Milan, Italy
    3. Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Milan, Italy
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  • Elena Brambilla,

    1. Neuroimmunology Unit, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan, Italy
    2. Institute of Experimental Neurology (InSpe), San Raffaele Scientific Institute, Milan, Italy
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  • Marcello Cadioli,

    1. Centro Eccellenza Risonanza Magnetica ad Alto Campo, San Raffaele Scientific Institute, Milan, Italy
    2. Philips Medical Systems, Eindhoven, The Netherlands
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  • Andrea Falini,

    1. Neuroradiology Unit, San Raffaele Scientific Institute, Milan, Italy
    2. Centro Eccellenza Risonanza Magnetica ad Alto Campo, San Raffaele Scientific Institute, Milan, Italy
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  • Giancarlo Comi,

    1. Institute of Experimental Neurology (InSpe), San Raffaele Scientific Institute, Milan, Italy
    2. Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Milan, Italy
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  • Giuseppe Scotti,

    1. Neuroradiology Unit, San Raffaele Scientific Institute, Milan, Italy
    2. Centro Eccellenza Risonanza Magnetica ad Alto Campo, San Raffaele Scientific Institute, Milan, Italy
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  • Gianvito Martino,

    1. Neuroimmunology Unit, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan, Italy
    2. Institute of Experimental Neurology (InSpe), San Raffaele Scientific Institute, Milan, Italy
    3. Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Milan, Italy
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  • Stefano Pluchino M.D., Ph.D.

    Corresponding author
    1. Neuroimmunology Unit, Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan, Italy
    2. Institute of Experimental Neurology (InSpe), San Raffaele Scientific Institute, Milan, Italy
    • Neuroimmunology Unit, Department of Biological and Technological Research (DIBIT)-San Raffaele Scientific Institute, Via Olgettina 58, 20123 Milan, Italy. Telephone: +39 02 26432791; Fax: +39 02 26434855
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Abstract

Eliciting the in situ accumulation and persistence patterns of stem cells following transplantation would provide critical insight toward human translation of stem cell-based therapies. To this end, we have developed a strategy to track neural stem/precursor cells (NPCs) in vivo using magnetic resonance (MR) imaging. Initially, we evaluated three different human-grade superparamagnetic iron oxide particles for labeling NPCs and found the optimal labeling to be achieved with Resovist. Next, we carried out in vivo experiments to monitor the accumulation of Resovist-labeled NPCs following i.v. injection in mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. With a human MR scanner, we were able to visualize transplanted cells as early as 24 hours post-transplantation in up to 80% of the brain demyelinating lesions. Interestingly, continued monitoring of transplanted mice indicated that labeled NPCs were still present 20 days postinjection. Neuropathological analysis confirmed the presence of transplanted NPCs exclusively in inflammatory demyelinating lesions and not in normal-appearing brain areas. Quantification of transplanted cells by means of MR-based ex vivo relaxometry (R2*) showed significantly higher R2* values in focal inflammatory brain lesions from EAE mice transplanted with labeled NPCs as compared with controls. Indeed, sensitive quantification of low numbers of NPCs accumulating into brain inflammatory lesions (33.3–164.4 cells per lesion; r2 = .998) was also obtained. These studies provide evidence that clinical-grade human MR can be used for noninvasive monitoring and quantification of NPC accumulation in the central nervous system upon systemic cell injection.

Disclosure of potential conflicts of interest is found at the end of this article.

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