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First published online June 28, 2007
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Submitted on January 15, 2007
Accepted on June 17, 2007

TECHNOLOGY DEVELOPMENT

Magnetic Resonance-based Tracking and Quantification of Intravenously-injected Neural Stem Cell Accumulation in the Brain of Mice With Experimental Multiple Sclerosis

Letterio S. Politi 1, Marco Bacigaluppi 2, Elena Brambilla 3, Marcello Cadioli 4, Andrea Falini 5, Giancarlo Comi 6, Giuseppe Scotti 1, Gianvito Martino 2, Stefano Pluchino 3*

1 Neuroradiology Unit, C.E.R.M.A.C. - Centro Eccellenza Risonanza Magnetica ad Alto Campo, Milan, Italy.
2 Neuroimmunology Unit, DiBiT, Institute of Experimental Neurology (InSpe), Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Milan, Italy.
3 Neuroimmunology Unit, DiBiT, Institute of Experimental Neurology (InSpe), Milan, Italy.
4 C.E.R.M.A.C. - Centro Eccellenza Risonanza Magnetica ad Alto Campo, Milan, Italy. Philips Medical Systems, Italy.
5 Neuroradiology Unit, C.E.R.M.A.C. -- Centro Eccellenza Risonanza Magnetica ad Alto Campo, Milan, Italy.
6 Institute of Experimental Neurology (InSpe), Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Milan, Italy.

* To whom correspondence should be addressed. E-mail: pluchino.stefano{at}hsr.it.


  Abstract

Eliciting the in situ accumulation and persistence patterns of stem cells following transplantation would provide critical insight towards 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 (SPIOs) for labelling NPCs, and found the optimal labelling to be achieved with Resovist®. Next, we carried out in vivo experiments to monitor the accumulation of Resovist®-labelled NPCs following intravenous 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 labelled NPCs were still present 20 days post-injection. 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 labelled NPCs, as compared to controls. Indeed, sensitive quantification of low numbers of NPCs accumulating into brain inflammatory lesions (33.3-164.4 cells/lesion; r2=0.998) was also obtained.

These studies provide evidence that clinical-grade human MR can be used for non-invasive monitoring and quantification of NPC accumulation in the CNS upon systemic cell injection.

 Key Words. Transplantation, neural stem cells, multiple sclerosis, magnetic resonance imaging, SPIO




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M. Neri, C. Maderna, C. Cavazzin, V. Deidda-Vigoriti, L. S. Politi, G. Scotti, P. Marzola, A. Sbarbati, A. L. Vescovi, and A. Gritti
Efficient In Vitro Labeling of Human Neural Precursor Cells with Superparamagnetic Iron Oxide Particles: Relevance for In Vivo Cell Tracking
Stem Cells, February 1, 2008; 26(2): 505 - 516.
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