Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis

Abstract

Widespread demyelination and axonal loss are the pathological hallmarks of multiple sclerosis. The multifocal nature of this chronic inflammatory disease of the central nervous system complicates cellular therapy and puts emphasis on both the donor cell origin and the route of cell transplantation. We established syngenic adult neural stem cell cultures and injected them into an animal model of multiple sclerosis—experimental autoimmune encephalomyelitis (EAE) in the mouse—either intravenously or intracerebroventricularly. In both cases, significant numbers of donor cells entered into demyelinating areas of the central nervous system and differentiated into mature brain cells. Within these areas, oligodendrocyte progenitors markedly increased, with many of them being of donor origin and actively remyelinating axons. Furthermore, a significant reduction of astrogliosis and a marked decrease in the extent of demyelination and axonal loss were observed in transplanted animals. The functional impairment caused by EAE was almost abolished in transplanted mice, both clinically and neurophysiologically. Thus, adult neural precursor cells promote multifocal remyelination and functional recovery after intravenous or intrathecal injection in a chronic model of multiple sclerosis.

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Figure 1: Distribution of nls-lacZ-labelled, syngenic neural precursors after i.c. (af) and i.v. injection (gk) in C57BL/6 mice.
Figure 2: Neural precursors contribute to remyelination of demyelinated axons in EAE mice.
Figure 3: Differentiation of engrafted neural precursors into mature neural cells in EAE mice.
Figure 4: I.c. or i.v. injection of neural precursors into EAE mice reduces glia scarring and modulates neurotrophic growth factor mRNA expression within the CNS.
Figure 5: I.v. and i.c. injection of neural precursors after disease onset (arrow) significantly improves clinical features in EAE mice.

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Acknowledgements

We thank L. De Filippis and L. Naldini for providing the lentiviral vectors and G. Constantin and B. Rossi for contributing to FACS analysis. We also thank C. Panzeri for technical help with confocal microscopy. This work was supported by the Italian Multiple Sclerosis Association (AISM), Myelin Project, European Union (EU), Fondazione Agarini and BMW Italia.

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Correspondence to Angelo L. Vescovi or Gianvito Martino.

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Pluchino, S., Quattrini, A., Brambilla, E. et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422, 688–694 (2003). https://doi.org/10.1038/nature01552

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