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Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism


In degenerative disorders of the central nervous system (CNS), transplantation of neural multipotent (stem) precursor cells (NPCs) is aimed at replacing damaged neural cells1,2. Here we show that in CNS inflammation, NPCs are able to promote neuroprotection by maintaining undifferentiated features and exerting unexpected immune-like functions. In a mouse model of chronic CNS inflammation, systemically injected adult syngeneic NPCs use constitutively activated integrins and functional chemokine receptors to selectively enter the inflamed CNS. These undifferentiated cells survive repeated episodes of CNS inflammation by accumulating within perivascular areas where reactive astrocytes, inflamed endothelial cells and encephalitogenic T cells produce neurogenic and gliogenic regulators. In perivascular CNS areas, surviving adult NPCs induce apoptosis of blood-borne CNS-infiltrating encephalitogenic T cells, thus protecting against chronic neural tissue loss as well as disease-related disability. These results indicate that undifferentiated adult NPCs have relevant therapeutic potential in chronic inflammatory CNS disorders because they display immune-like functions that promote long-lasting neuroprotection.

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Figure 1: aNPCs transplanted intravenously persist in inflamed perivascular areas of the CNS for up to three months after transplantation in R-EAE mice.
Figure 2: Stem cell regulators co-localize with intravenously injected aNPCs that persist in perivascular areas of the CNS in R-EAE mice.
Figure 3: aNPCs constitutively expressing VLA-4 and chemokine receptors accumulate around inflamed CNS microvessels in R-EAE mice.
Figure 4: aNPCs induce apoptosis of encephalitogenic T cells in vitro and in vivo.

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  1. Lindvall, O., Kokaia, Z. & Martinez-Serrano, A. Stem cell therapy for human neurodegenerative disorders-how to make it work. Nature Med. 10 (suppl.), S42–S50 (2004)

    Article  Google Scholar 

  2. Pluchino, S. et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422, 688–694 (2003)

    Article  ADS  CAS  Google Scholar 

  3. McRae, B. L. et al. Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein. J. Neuroimmunol. 38, 229–240 (1992)

    Article  CAS  Google Scholar 

  4. Parras, C. M. et al. Mash1 specifies neurons and oligodendrocytes in the postnatal brain. EMBO J. 23, 4495–4505 (2004)

    Article  CAS  Google Scholar 

  5. Fukuda, S. et al. Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus. J. Neurosci. 23, 9357–9366 (2003)

    Article  CAS  Google Scholar 

  6. Lois, C., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Chain migration of neuronal precursors. Science 271, 978–981 (1996)

    Article  ADS  CAS  Google Scholar 

  7. Wichterle, H., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Direct evidence for homotypic, glia-independent neuronal migration. Neuron 18, 779–791 (1997)

    Article  CAS  Google Scholar 

  8. Alvarez-Buylla, A. & Lim, D. A. For the long run: maintaining germinal niches in the adult brain. Neuron 41, 683–686 (2004)

    Article  CAS  Google Scholar 

  9. Jin, K. et al. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl Acad. Sci. USA 99, 11946–11950 (2002)

    Article  ADS  CAS  Google Scholar 

  10. Constantin, G. et al. Chemokines trigger immediate β2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow. Immunity 13, 759–769 (2000)

    Article  CAS  Google Scholar 

  11. Constantin, G., Laudanna, C., Brocke, S. & Butcher, E. C. Inhibition of experimental autoimmune encephalomyelitis by a tyrosine kinase inhibitor. J. Immunol. 162, 1144–1149 (1999)

    CAS  PubMed  Google Scholar 

  12. Alt, C., Laschinger, M. & Engelhardt, B. Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood–brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis. Eur. J. Immunol. 32, 2133–2144 (2002)

    Article  CAS  Google Scholar 

  13. Karpus, W. J. & Kennedy, K. J. MIP-1α and MCP-1 differentially regulate acute and relapsing autoimmune encephalomyelitis as well as Th1/Th2 lymphocyte differentiation. J. Leukoc. Biol. 62, 681–687 (1997)

    Article  CAS  Google Scholar 

  14. 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)

    Article  CAS  Google Scholar 

  15. Weishaupt, A. et al. Molecular mechanisms of high-dose antigen therapy in experimental autoimmune encephalomyelitis: rapid induction of Th1-type cytokines and inducible nitric oxide synthase. J. Immunol. 165, 7157–7163 (2000)

    Article  CAS  Google Scholar 

  16. Marsden, V. S. & Strasser, A. Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more. Annu. Rev. Immunol. 21, 71–105 (2003)

    Article  CAS  Google Scholar 

  17. Ricci-Vitiani, L. et al. Absence of caspase 8 and high expression of PED protect primitive neural cells from cell death. J. Exp. Med. 200, 1257–1266 (2004)

    Article  CAS  Google Scholar 

  18. Schere-Levy, C. et al. Leukemia inhibitory factor induces apoptosis of the mammary epithelial cells and participates in mouse mammary gland involution. Exp. Cell Res. 282, 35–47 (2003)

    Article  CAS  Google Scholar 

  19. Tarrant, T. K. et al. Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis. J. Exp. Med. 189, 219–230 (1999)

    Article  CAS  Google Scholar 

  20. Pender, M. P. & Rist, M. J. Apoptosis of inflammatory cells in immune control of the nervous system: role of glia. Glia 36, 137–144 (2001)

    Article  CAS  Google Scholar 

  21. Chu, K., Kim, M., Jeong, S. W., Kim, S. U. & Yoon, B. W. Human neural stem cells can migrate, differentiate, and integrate after intravenous transplantation in adult rats with transient forebrain ischemia. Neurosci. Lett. 343, 129–133 (2003)

    Article  CAS  Google Scholar 

  22. Akiyama, Y. et al. Transplantation of clonal neural precursor cells derived from adult human brain establishes functional peripheral myelin in the rat spinal cord. Exp. Neurol. 167, 27–39 (2001)

    Article  CAS  Google Scholar 

  23. Vandenbark, A. A. et al. Differential susceptibility of human Th1 versus Th2 cells to induction of anergy and apoptosis by ECDI/antigen-coupled antigen-presenting cells. Int. Immunol. 12, 57–66 (2000)

    Article  CAS  Google Scholar 

  24. Zhang, X. et al. Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J. Exp. Med. 185, 1837–1849 (1997)

    Article  CAS  Google Scholar 

  25. Merkle, F. T., Tramontin, A. D., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Radial glia give rise to adult neural stem cells in the subventricular zone. Proc. Natl Acad. Sci. USA 101, 17528–17532 (2004)

    Article  ADS  CAS  Google Scholar 

  26. Constantin, G., Laudanna, C. & Butcher, E. C. Novel method for following lymphocyte traffic in mice using [3H]glycerol labeling. J. Immunol. Methods 203, 35–44 (1997)

    Article  CAS  Google Scholar 

  27. Lazarini, F. et al. Differential signalling of the chemokine receptor CXCR4 by stromal cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes. Eur. J. Neurosci. 12, 117–125 (2000)

    Article  CAS  Google Scholar 

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We wish to thank R. Galli, A. Gritti, M. Muzio, A. Vescovi and L. Ricci-Vitiani for discussions. We are grateful to F. Mavilio for critically discussing the manuscript. We acknowledge the technical help of S. Bach, S. Bucello, E. Butti, C. Covino, R. Molteni, A. Palini and C. Sciorati. S.P. is the recipient of a fellowship from the National Multiple Sclerosis Society (NMSS). L.Z. is the recipient of a fellowship from The Myelin Project (TMP). This work was supported in part by the Italian Minister of Health, the Italian Multiple Sclerosis Foundation (FISM), NMSS and TMP.

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Correspondence to Gianvito Martino.

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Supplementary information

Supplementary Figure S1

I.v.-injection of syngenic aNPCs reduces clinical relapses in R-EAE mice. (PDF 57 kb)

Supplementary Figure S2

I.v.-injected syngenic aNPCs persist within CNS perivascular areas of R-EAE mice. (PDF 13711 kb)

Supplementary Figure S3

Confocal images showing co-localization experiments performed in aNPC-transplanted R-EAE mice 106 dpi. (PDF 4000 kb)

Supplementary Figure S4

Perivascular CNS areas from R-EAE mice express stem cell regulators and contain activated microglia. (PDF 17263 kb)

Supplementary Figure S5

Stem cell regulators co-localize with i.v.-injected aNPCs persisting within perivascular CNS areas from R-EAE mice. (PDF 17596 kb)

Supplementary Figure S6

aNPCs constitutively express VLA-4 and adhere to VCAM-1 expressing CNS inflamed microvessels from C57Bl/6 mice with chronic progressive EAE. (PDF 555 kb)

Supplementary Figure S7

aNPCs express wide range of functional pro-inflammatory chemokine receptors. (PDF 81 kb)

Supplementary Figure S8

In vitro and in vivo analysis of CD3+ cells undergoing apoptosis. (PDF 11511 kb)

Supplementary Figure S9

Expression of regulators of stem cell proliferation and differentiation, immune molecules and trophic factors by aNPCs. (PDF 55 kb)

Supplementary Figures Legends

Full text legends to accompany the above Supplementary Figures. (DOC 39 kb)

Supplementary Video S1

Animated 3D reconstruction of a CNS perivascular area showing persistence of β-gal+ cells in close contact to endothelial cells producing BMP-4. (MOV 235 kb)

Supplementary Video S2

Animated 3D reconstruction of a CNS perivascular area showing persistence of β-gal+ cells in close contact with CNS-infiltrating CD45+ cells producing Noggin. (MOV 246 kb)

Supplementary Video S3

Animated 3D reconstruction of a β-gal+ cell expressing PSA-NCAM and incorporating BrdU 106 dpi. (MOV 96 kb)

Supplementary Video S4

Animated 3D reconstruction of a β-gal+ cell incorporating BrdU 106 dpi. (MOV 134 kb)

Supplementary Video Legends (DOC 37 kb)

Supplementary Methods

Additional descriptions of methods used in this study. (DOC 63 kb)

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Pluchino, S., Zanotti, L., Rossi, B. et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436, 266–271 (2005).

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