Grafts of brain-derived neurotrophic factor and neurotrophin 3-transduced primate Schwann cells lead to functional recovery of the demyelinated mouse spinal cord.
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.
Girard
Christelle
C
Institut National de la Santé et de la Recherche Médicale Unité 546, Centre Hospitalier Universitaire Pitié-Salpêtrière, 75634 Paris Cedex 13, France.
Bemelmans
Alexis-Pierre
AP
Dufour
Noëlle
N
Mallet
Jacques
J
Bachelin
Corinne
C
Nait-Oumesmar
Brahim
B
Baron-Van Evercooren
Anne
A
Lachapelle
François
F
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology*; D012583:Schwann Cells / Q000378:metabolism / Q000637:transplantation*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D014161:Transduction, Genetic / Q000379:methods; D019737:Transplants
D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3