Lentiviral-mediated silencing of glial fibrillary acidic protein and vimentin promotes anatomical plasticity and functional recovery after spinal cord injury

Autor: Desclaux, Mathieu, Perrin, Florence, Do-Thi, Anh, Prieto-Cappellini, Monica, Gimenez y Ribotta, Minerva, Mallet, Jacques, Privat, Alain
Přispěvatelé: Centre National de la Recherche Scientifique (France), Université Pierre et Marie Curie, Conseil régional d'Aquitaine, Institut du Cerveau et de la Moelle Epinière (France), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: Journal of Neuroscience Research
Journal of Neuroscience Research, Wiley, 2015, 93 (1), pp.43-55. ⟨10.1002/jnr.23468⟩
ISSN: 0360-4012
1097-4547
DOI: 10.1002/jnr.23468⟩
Popis: 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.
Contract grant sponsor: Centre National de la Recherche Scientifique(CNRS); Contract grant sponsor: Institut National de la Sant eetdelaRecherche M edicale (INSERM); Contract grant sponsor: Pierre et MarieCurie University (UPMC); Contract grant sponsor: Verticale; Contractgrant sponsor: Demain Debout Aquitaine; Contract grant sponsor: Insti-tut de Recherche sur la Moelle epinie`re et l’Enc ephale (IRME)
Databáze: OpenAIRE
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