title: Combination of grafted Schwann cells and lentiviral-mediated prevention of glial scar formation improve recovery of spinal cord injured rats.
abstract: The present study was intended to combine three therapeutic approaches in a well-defined rat model of spinal cord injury, a lateral hemisection at thoracic level. A guidance channel was implanted at the lesion site. This channel was seeded with native Schwann cells or Schwann cells that had been previously transduced with a lentiviral vector carrying the GDNF gene. Thereafter, these experiences were reproduced in animals injected with lentiviral vectors carrying a shRNA for GFAP (Lv-shGFAP), which has recently been shown to block glial scar formation. Functional evaluations showed that Lv-shGFAP induced a significant improvement in recovery in animals grafted with Schwann cells. Histological studies demonstrated the outgrowth of axons in the guidance channel containing Schwann cells transduced or not with GDNF. This axonal growth was enhanced in rats receiving Lv-shGFAP vector. Also, a significant increase of serotonergic innervation of the injured hemicord, distal to the lesion, was found only in animals treated with Lv-shGFAP vectors. Importantly, this study confirms that glial scar formation is a major impediment for axonal sprouting after spinal cord injury, and emphasizes the importance of serotonergic innervation for locomotor function. Moreover we show a significant additive effect of a combinatorial approach to axonal regeneration in the injured spinal cord.
authors.affiliation: Biotechnology and Biotherapy laboratory, Institut du Cerveau et de la Moelle épinière (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, Institut National de la Santé et de la Recherche Medicale (INSERM) UMRS975, Sorbonne Universités, Université Pierre & Marie Curie (UPMC)-Hôpital de la Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France.
authors.forename: Anh
authors.initials: A
authors.lastname: Do-Thi
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U1051, Physiopathologie et Thérapie des Déficits Sensoriels et Moteurs, Institut des Neurosciences de Montpellier (INM), University of Montpellier, Montpellier F-34091 Cedex 5, France; IKERBASQUE Basque Foundation for Science, Department of Neuroscience, University of the Basque Country UPV/EHU, E-48011 Bilbao, Spain. Electronic address: florence.perrin@inserm.fr.
authors.forename: Florence E
authors.initials: FE
authors.lastname: Perrin
authors.affiliation: Biotechnology and Biotherapy laboratory, Institut du Cerveau et de la Moelle épinière (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, Institut National de la Santé et de la Recherche Medicale (INSERM) UMRS975, Sorbonne Universités, Université Pierre & Marie Curie (UPMC)-Hôpital de la Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Desclaux
authors.affiliation: Biotechnology and Biotherapy laboratory, Institut du Cerveau et de la Moelle épinière (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, Institut National de la Santé et de la Recherche Medicale (INSERM) UMRS975, Sorbonne Universités, Université Pierre & Marie Curie (UPMC)-Hôpital de la Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Saillour
authors.affiliation: Biotechnology and Biotherapy laboratory, Institut du Cerveau et de la Moelle épinière (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, Institut National de la Santé et de la Recherche Medicale (INSERM) UMRS975, Sorbonne Universités, Université Pierre & Marie Curie (UPMC)-Hôpital de la Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France.
authors.forename: Lahouari
authors.initials: L
authors.lastname: Amar
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U1051, Physiopathologie et Thérapie des Déficits Sensoriels et Moteurs, Institut des Neurosciences de Montpellier (INM), University of Montpellier, Montpellier F-34091 Cedex 5, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Privat
authors.affiliation: Biotechnology and Biotherapy laboratory, Institut du Cerveau et de la Moelle épinière (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, Institut National de la Santé et de la Recherche Medicale (INSERM) UMRS975, Sorbonne Universités, Université Pierre & Marie Curie (UPMC)-Hôpital de la Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France. Electronic address: malletj@neurosurg.ucsf.edu.
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
mesh_terms: D000818:Animals; D002470:Cell Survival; D002921:Cicatrix / Q000473:pathology; D005260:Female; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008124:Locomotion; D009457:Neuroglia / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012583:Schwann Cells / Q000637:transplantation*; D059326:Serotonergic Neurons / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000628:therapy*
chemical_list: C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D034741:RNA, Small Interfering
keywords: Functional recovery; GDNF; GFAP inhibition; Glial scar; Lentiviral vector; Schwann cells implantation; Spinal cord injury