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The Journal of Neuroscience, August 31, 2005, 25(35):7924-7933; doi:10.1523/JNEUROSCI.4890-04.2005

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Development/Plasticity/Repair
Grafts of Brain-Derived Neurotrophic Factor and Neurotrophin 3-Transduced Primate Schwann Cells Lead to Functional Recovery of the Demyelinated Mouse Spinal Cord

Christelle Girard,¹ Alexis-Pierre Bemelmans,² Noëlle Dufour,² Jacques Mallet,² Corinne Bachelin,¹ Brahim Nait-Oumesmar,¹ Anne Baron-Van Evercooren,¹ and François Lachapelle¹

¹Institut National de la Santé et de la Recherche Médicale Unité 546, Laboratoire des Affections de la Myéline et des Canaux Ioniques Musculaires, and ²Centre National de la Recherche Scientifique Unité 7091, Institut Fédératif de Recherche 70, Centre Hospitalier Universitaire Pitié-Salpêtrière, 75634 Paris Cedex 13, France

Experimental studies provided overwhelming proof that transplants of myelin-forming cells achieve efficient remyelination in the CNS. Among cellular candidates, Schwann cells can be used for autologous transplantation to ensure robust remyelination of lesions and to deliver therapeutic factors in the CNS. In the present study, macaque Schwann cells expressing green fluorescent protein (GFP) were infected with human immunodeficiency virus-derived vectors overexpressing brain-derived neurotrophic factor (BDNF) or Neurotrophin 3 (NT-3), two neurotrophins that also modulate glial cell biology. The ability of transgenic Schwann cells to secrete growth factors was assessed by ELISA and showed 35- and 62-fold increases in BDNF and NT-3, respectively, in transduced macaque Schwann cell supernatants. Conditioned media of BDNF- and NT-3-transduced Schwann cells reduced Schwann cell proliferation and favored their differentiation in vitro. Transgenic cells were grafted in demyelinated spinal cords of adult nude mice. Two behavioral assays showed that NT-3- and BDNF-transduced Schwann cells promoted faster and stronger functional recovery than GFP-transduced Schwann cells. Morphological analysis indicated that functional recovery correlated with enhanced proliferation and differentiation of resident oligodendrocyte progenitors and enhanced oligodendrocyte and Schwann cell differentiation. Moreover, NT-3-transduced Schwann cells provided neuroprotection and reduced astrogliosis. These results underline the potential therapeutic benefit of combining neuroprotection and activation of myelin-forming cells to restore altered functions in demyelinating diseases of the CNS.

Key words: primate; Schwann cell; neurotrophins; remyelination; neuroprotection; astrogliosis

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Received Dec 1, 2004; revised June 13, 2005; accepted June 14, 2005.

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