Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates

Authors

  • Stefano Pluchino MD, PhD,

    Corresponding author
    1. Neuroimmunology Unit, San Raffaele Scientific Institute, Milan, Italy
    2. Institute of Experimental Neurology (InSpe), San Raffaele Scientific Institute, Milan, Italy
    3. CNS Repair Unit, San Raffaele Scientific Institute, Milan, Italy
    • via Olgettina 58, Milano 20132, Italy
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    • authors contributed equally.

  • Angela Gritti PhD,

    1. Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, Milan, Italy
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    • authors contributed equally.

  • Erwin Blezer PhD,

    1. Image Science Institute, University Medical Centre Utrecht, Utrecht, The Netherlands
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  • Stefano Amadio MD,

    1. Department of Neurology and Clinical Neurophysiology, San Raffaele Scientific Institute, Milan, Italy
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  • Elena Brambilla BSc,

    1. Neuroimmunology Unit, San Raffaele Scientific Institute, Milan, Italy
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  • Giovanna Borsellino MD, PhD,

    1. Neuroimmunology Unit, European Brain Research Institute, Santa Lucia Foundation, via del Fosso di Fiorano, Rome, Italy
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  • Chiara Cossetti BSc,

    1. Neuroimmunology Unit, San Raffaele Scientific Institute, Milan, Italy
    2. Institute of Experimental Neurology (InSpe), San Raffaele Scientific Institute, Milan, Italy
    3. Instituto de Ciências Biomedicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
    4. CNS Repair Unit, San Raffaele Scientific Institute, Milan, Italy
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  • Ubaldo Del Carro MD,

    1. Department of Neurology and Clinical Neurophysiology, San Raffaele Scientific Institute, Milan, Italy
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  • Giancarlo Comi MD,

    1. Institute of Experimental Neurology (InSpe), San Raffaele Scientific Institute, Milan, Italy
    2. Department of Neurology and Clinical Neurophysiology, San Raffaele Scientific Institute, Milan, Italy
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  • Bert 't Hart PhD,

    1. Department of Immunobiology, Biomedical Primate Research Center (BPRC), Rijswijk, The Netherlands
    2. Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands
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  • Angelo Vescovi PhD,

    Corresponding author
    1. Bioscience and Biotechnology Department and Unit of Cancer Stem Cell Biology, StemGen SpA, University of Milan-Bicocca, Milan, Italy
    • via Olgettina 58, Milano 20132, Italy
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  • Gianvito Martino MD

    Corresponding author
    1. Neuroimmunology Unit, San Raffaele Scientific Institute, Milan, Italy
    2. Institute of Experimental Neurology (InSpe), San Raffaele Scientific Institute, Milan, Italy
    3. Department of Neurology and Clinical Neurophysiology, San Raffaele Scientific Institute, Milan, Italy
    • via Olgettina 58, Milano 20132, Italy
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  • Potential conflict of interest: Nothing to report.

Abstract

Objective

Transplanted neural stem/precursor cells (NPCs) display peculiar therapeutic plasticity in vivo. Although the replacement of cells was first expected as the prime therapeutic mechanism of stem cells in regenerative medicine, it is now clear that transplanted NPCs simultaneously instruct several therapeutic mechanisms, among which replacement of cells might not necessarily prevail. A comprehensive understanding of the mechanism(s) by which NPCs exert their therapeutic plasticity is lacking. This study was designed as a preclinical approach to test the feasibility of human NPC transplantation in an outbreed nonhuman primate experimental autoimmune encephalomyelitis (EAE) model approximating the clinical and complex neuropathological situation of human multiple sclerosis (MS) more closely than EAE in the standard laboratory rodent.

Methods

We examined the safety and efficacy of the intravenous (IV) and intrathecal (IT) administration of human NPCs in common marmosets affected by human myelin oligodendrocyte glycoprotein 1-125–induced EAE. Treatment commenced upon the occurrence of detectable brain lesions on a 4.7T spectrometer.

Results

EAE marmosets injected IV or IT with NPCs accumulated lower disability and displayed increased survival, as compared with sham-treated controls. Transplanted NPCs persisted within the host central nervous system (CNS), but were also found in draining lymph nodes, for up to 3 months after transplantation and exhibited remarkable immune regulatory capacity in vitro.

Interpretation

Herein, we provide the first evidence that human CNS stem cells ameliorate EAE in nonhuman primates without overt side effects. Immune regulation (rather than neural differentiation) is suggested as the major putative mechanism by which NPCs ameliorate EAE in vivo. Our findings represent a critical step toward the clinical use of human NPCs in MS. Ann Neurol 2009;66:343–354

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