title: Lentiviral-mediated silencing of glial fibrillary acidic protein and vimentin promotes anatomical plasticity and functional recovery after spinal cord injury.
abstract: In spinal cord injury (SCI), absence of functional recovery and lack of spontaneous axonal regeneration are attributed, among other factors, to the formation of a glial scar that forms both physical and chemical barriers. The glial scar is composed mainly of reactive astrocytes that overexpress two intermediate filament proteins, glial fibrillary acidic protein (GFAP) and vimentin (VIM). To promote regeneration and sprouting of spared axons after spinal cord trauma and with the objective of translation to clinics, we designed an original in vivo gene transfer strategy to reduce glial scar formation after SCI, based on the RNA interference (RNAi)-mediated inhibition of GFAP and VIM. We first show that direct injection of lentiviral vectors expressing short hairpin RNA (shRNA) against GFAP and VIM in a mouse model of SCI allows efficient and specific targeting of astrocytes. We then demonstrate that the lentiviral-mediated and stable expression of shGFAP and shVIM leads to a strong reduction of astrogliosis, improves functional motor recovery, and promotes axonal regrowth and sprouting of spared axons. This study thus examplifies how the nonneuronal environment might be a major target within the lesioned central nervous system to promote axonal regeneration (and sprouting) and validates the use of lentiviral-mediated RNAi in SCI.
authors.affiliation: Biotechnology and Biotherapy, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere, Centre National de la Recherche Scientifique (CNRS) UMR 7225, Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 975, Université Pierre et Marie Curie (UPMC), Hôpital de la Pitié Salpêtrière, Paris, France; Columbia University, Department of Pathology and Cell Biology Project A.L.S.-Jenifer Estess Laboratory for Stem Cell Research, New York, New York.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Desclaux
authors.forename: Florence E
authors.initials: FE
authors.lastname: Perrin
authors.forename: Anh
authors.initials: A
authors.lastname: Do-Thi
authors.forename: Monica
authors.initials: M
authors.lastname: Prieto-Cappellini
authors.forename: Minerva
authors.initials: M
authors.lastname: Gimenez Y Ribotta
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.forename: Alain
authors.initials: A
authors.lastname: Privat
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001369:Axons / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005822:Genetic Vectors / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D008124:Locomotion / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014746:Vimentin / Q000235:genetics / Q000378:metabolism*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D034741:RNA, Small Interfering; D014746:Vimentin; D012701:Serotonin
keywords: astrocyte; functional recovery; gene transfer; glial scar; spinal cord injury repair