title: A Delay between Motor Cortex Lesions and Neuronal Transplantation Enhances Graft Integration and Improves Repair and Recovery.
abstract: We previously reported that embryonic motor cortical neurons transplanted immediately after lesions in the adult mouse motor cortex restored damaged motor cortical pathways. A critical barrier hindering the application of transplantation strategies for a wide range of traumatic injuries is the determination of a suitable time window for therapeutic intervention. Here, we report that a 1 week delay between the lesion and transplantation significantly enhances graft vascularization, survival, and proliferation of grafted cells. More importantly, the delay dramatically increases the density of projections developed by grafted neurons and improves functional repair and recovery as assessed by intravital dynamic imaging and behavioral tests. These findings open new avenues in cell transplantation strategies as they indicate successful brain repair may occur following delayed transplantation.SIGNIFICANCE STATEMENTCell transplantation represents a promising therapy for cortical trauma. We previously reported that embryonic motor cortical neurons transplanted immediately after lesions in the adult mouse motor cortex restored damaged cortical pathways. A critical barrier hindering the application of transplantation strategies for a wide range of traumatic injuries is the determination of a suitable time window for therapeutic intervention. We demonstrate that a 1 week delay between the lesion and transplantation significantly enhances graft vascularization, survival, proliferation, and the density of the projections developed by grafted neurons. More importantly, the delay has a beneficial impact on functional repair and recovery. These results impact the effectiveness of transplantation strategies in a wide range of traumatic injuries for which therapeutic intervention is not immediately feasible.
authors.affiliation: INSERM U1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, 86022 Poitiers Cedex, France.|Université de Poitiers, U1084, 86073 Poitiers Cedex, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Péron
authors.affiliation: INSERM U1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, 86022 Poitiers Cedex, France.|Université de Poitiers, U1084, 86073 Poitiers Cedex, France.
authors.forename: Marine
authors.identifier: 0000-0002-5936-9932
authors.initials: M
authors.lastname: Droguerre
authors.affiliation: CNRS, UMR 7289, ImaPath, Institut de Neurosciences de la Timone, Faculté de Médecine, 13005 Marseille, France.|Aix-Marseille Université, 13284 Marseille Cedex 07, France, and.
authors.forename: Franck
authors.initials: F
authors.lastname: Debarbieux
authors.affiliation: INSERM U1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, 86022 Poitiers Cedex, France.|Université de Poitiers, U1084, 86073 Poitiers Cedex, France.
authors.forename: Nissrine
authors.identifier: 0000-0001-8301-3170
authors.initials: N
authors.lastname: Ballout
authors.affiliation: INSERM U1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, 86022 Poitiers Cedex, France.|Université de Poitiers, U1084, 86073 Poitiers Cedex, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Benoit-Marand
authors.affiliation: INSERM U1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, 86022 Poitiers Cedex, France.|Université de Poitiers, U1084, 86073 Poitiers Cedex, France.
authors.forename: Maureen
authors.identifier: 0000-0003-4354-7455
authors.initials: M
authors.lastname: Francheteau
authors.affiliation: INSERM U1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, 86022 Poitiers Cedex, France.|Université de Poitiers, U1084, 86073 Poitiers Cedex, France.
authors.forename: Sébastien
authors.identifier: 0000-0002-4373-2135
authors.initials: S
authors.lastname: Brot
authors.affiliation: CNRS, UMR 7289, ImaPath, Institut de Neurosciences de la Timone, Faculté de Médecine, 13005 Marseille, France.|Aix-Marseille Université, 13284 Marseille Cedex 07, France, and.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Rougon
authors.affiliation: INSERM U1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, 86022 Poitiers Cedex, France.|Université de Poitiers, U1084, 86073 Poitiers Cedex, France.|CHU de Poitiers, 86021 Poitiers Cedex, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Jaber
authors.affiliation: INSERM U1084, Experimental and Clinical Neurosciences Laboratory, Cellular Therapies in Brain Diseases Group, University of Poitiers, 86022 Poitiers Cedex, France, afsaneh.gaillard@univ-poitiers.fr.|Université de Poitiers, U1084, 86073 Poitiers Cedex, France.
authors.forename: Afsaneh
authors.identifier: 0000-0002-9375-6506
authors.initials: A
authors.lastname: Gaillard
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000473:pathology / Q000601:surgery*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009044:Motor Cortex / Q000473:pathology*; D009046:Motor Neurons / Q000502:physiology*; D009069:Movement Disorders / Q000209:etiology / Q000601:surgery; D009416:Nerve Regeneration / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000379:methods*
chemical_list: D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine
keywords: cortical injury; delay; functional recovery; neuroanatomical repair; transplantation