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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lucchinetti, C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47, 707–717 (2000)
Hemmer, B., Archelos, J. J. & Hartung, H. P. New concepts in the immunopathogenesis of multiple sclerosis. Nature Rev. Neurosci. 3, 291–301 (2002)
Archer, D. R., Cuddon, P. A., Lipsitz, D. & Duncan, I. D. Myelination of the canine central nervous system by glial cell transplantation: a model for repair of human myelin disease. Nature Med. 3, 54–59 (1997)
Groves, A. K. et al. Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 362, 453–455 (1993)
Blakemore, W. F. Remyelination of CNS axons by Schwann cells transplanted from the sciatic nerve. Nature 266, 68–69 (1977)
Imaizumi, T., Lankford, K. L., Burton, W. V., Fodor, W. L. & Kocsis, J. D. Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord. Nature Biotechnol. 18, 949–953 (2000)
Jefferson, S. et al. Inhibition of oligodendrocyte precursor motility by oligodendrocyte processes: implications for transplantation-based approaches to multiple sclerosis. Mult. Scler. 3, 162–167 (1997)
Franklin, R. J. & Blakemore, W. F. To what extent is oligodendrocyte progenitor migration a limiting factor in the remyelination of multiple sclerosis lesions? Mult. Scler. 3, 84–87 (1997)
Clarke, D. & Frisen, J. Differentiation potential of adult stem cells. Curr. Opin. Genet. Dev. 11, 575–580 (2001)
Horner, P. J. & Gage, F. H. Regenerating the damaged central nervous system. Nature 407, 963–970 (2000)
Teng, Y. D. et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc. Natl Acad. Sci. USA 99, 3024–3029 (2002)
Gritti, A. et al. Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain. J. Neurosci. 19, 3287–3297 (1999)
Galli, R. et al. Emx2 regulates the proliferation of stem cells of the adult mammalian central nervous system. Development 129, 1633–1644 (2002)
Deckert-Schluter, M., Schluter, D., Hof, H., Wiestler, O. D. & Lassmann, H. Differential expression of ICAM-1, VCAM-1 and their ligands LFA-1, Mac-1, CD43, VLA-4, and MHC class II antigens in murine Toxoplasma encephalitis: a light microscopic and ultrastructural immunohistochemical study. J. Neuropathol. Exp. Neurol. 53, 457–468 (1994)
Butcher, E. C. & Picker, L. J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996)
Brocke, S., Piercy, C., Steinman, L., Weissman, I. L. & Veromaa, T. Antibodies to CD44 and integrin α4, but not L-selectin, prevent central nervous system inflammation and experimental encephalomyelitis by blocking secondary leukocyte recruitment. Proc. Natl Acad. Sci. USA 96, 6896–6901 (1999)
Del Maschio, A. et al. Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM). J. Exp. Med. 190, 1351–1356 (1999)
Furlan, R. et al. Intrathecal delivery of IFN-γ protects C57BL/6 mice from chronic-progressive experimental autoimmune encephalomyelitis by increasing apoptosis of central nervous system-infiltrating lymphocytes. J. Immunol. 167, 1821–1829 (2001)
Gensert, J. M. & Goldman, J. E. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron 19, 197–203 (1997)
Eclancher, F., Kehrli, P., Labourdette, G. & Sensenbrenner, M. Basic fibroblast growth factor (bFGF) injection activates the glial reaction in the injured adult rat brain. Brain Res. 737, 201–214 (1996)
Moon, L. D. & Fawcett, J. W. Reduction in CNS scar formation without concomitant increase in axon regeneration following treatment of adult rat brain with a combination of antibodies to TGFβ1 and β2. Eur. J. Neurosci. 14, 1667–1677 (2001)
Linker, R. A. et al. CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nature Med. 8, 620–624 (2002)
Alexander, J. S. & Elrod, J. W. Extracellular matrix, junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation. J. Anat. 200, 561–574 (2002)
Temple, S. The development of neural stem cells. Science 414, 112–117 (2001)
Franklin, R. J. Why does remyelination fail in multiple sclerosis? Nature Rev. Neurosci. 3, 705–714 (2002)
Kim, J. H. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50–56 (2002)
Aboody, K. S. et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc. Natl Acad. Sci. USA 97, 12846–12851 (2000)
Choop, M. & Li, Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol. 1, 92–100 (2002)
Learish, R. D., Brustle, O., Zhang, S. C. & Duncan, I. D. Intraventricular transplantation of oligodendrocyte progenitors into a fetal myelin mutant results in widespread formation of myelin. Ann. Neurol. 46, 716–722 (1999)
Chen, J. et al. Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J. Neurol. Sci. 189, 49–57 (2001)
Follenzi, A., Ailles, L. E., Bakovic, S., Geuna, M. & Naldini, L. Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences. Nature Genet. 25, 217–222 (2000)
Feltri, M. L. et al. Conditional disruption of beta1 integrin in Schwann cells impedes interactions with axons. J. Cell. Biol. 156, 199–209 (2002)
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.
The authors declare that they have no competing financial interests.
About this article
Cite this article
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
Skeletal muscle stem cells confer maturing macrophages anti‐inflammatory properties through insulin‐like growth factor‐2
STEM CELLS Translational Medicine (2020)
Continuous Immune-Modulatory Effects of Human Olig2+ Precursor Cells Attenuating a Chronic-Active Model of Multiple Sclerosis
Molecular Neurobiology (2020)
Transplantation of IFN-γ Primed hUCMSCs Significantly Improved Outcomes of Experimental Autoimmune Encephalomyelitis in a Mouse Model
Neurochemical Research (2020)
Olfactory ensheathing cells improve the survival of porcine neural xenografts in a Parkinsonian rat model
Brain Research (2020)