title: Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury.
abstract: Transplantation of neural progenitor cells (NPCs) may be a potential treatment strategy for traumatic brain injury (TBI) due to their intrinsic advantages, including the secretion of neurotrophins. Neurotrophins are critical for neuronal survival and repair, but their clinical use is limited. In this study, we hypothesized that pericontusional transplantation of NPCs genetically modified to secrete a synthetic, human multineurotrophin (MNTS1) would overcome some of the limitations of traditional neurotrophin therapy. MNTS1 is a multifunctional neurotrophin that binds all three tropomyosin-related kinase (Trk) receptors, recapitulating the prosurvival activity of 3 endogenous mature neurotrophins. NPCs obtained from rat fetuses at E15 were transduced with lentiviral vectors containing MNTS1 and GFP constructs (MNTS1-NPCs) or fluorescent constructs alone (control GFP-NPCs). Adult rats received fluid percussion-induced TBI or sham surgery. Animals were transplanted 1week later with control GFP-NPCs, MNTS1-NPCs, or injected with saline (vehicle). At five weeks, animals were evaluated for hippocampal-dependent spatial memory. Six weeks post-surgery, we observed significant survival and neuronal differentiation of MNTS1-NPCs and injury-activated tropism toward contused regions. NPCs displayed processes that extended into several remote structures, including the hippocampus and contralateral cortex. Both GFP- and MNTS1-NPCs conferred significant preservation of pericontusional host tissues and enhanced hippocampal neurogenesis. NPC transplantation improved spatial memory capacity on the Morris water maze (MWM) task. Transplant recipients exhibited escape latencies approximately half that of injured vehicle controls. While we observed greater transplant survival and neuronal differentiation of MNTS1-NPCs, our collective findings suggest that MNTS1 may be superfluous in terms of preserving the cytoarchitecture and rescuing behavioral deficits given the lack of significant difference between MNTS1- and GFP-control transplanted groups. Nevertheless, our overall findings support the potential of syngeneic NPC transplantation to enhance endogenous neuroreparative responses and may therefore be an effective treatment for TBI.
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA. Electronic address: Moconnell2@med.miami.edu.
authors.forename: Meghan O
authors.initials: MO
authors.lastname: Blaya
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA. Electronic address: ptsoulfa@med.miami.edu.
authors.forename: Pantelis
authors.initials: P
authors.lastname: Tsoulfas
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA; Bruce W. Carter Department of Veterans Affairs Medical Center, 1201 NW 16th Street, Miami, FL 33125, USA. Electronic address: Hbramlett@med.miami.edu.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bramlett
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA. Electronic address: ddietrich@miami.edu.
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001362:Avoidance Learning; D001930:Brain Injuries / Q000150:complications* / Q000601:surgery*; D002452:Cell Count; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology* / Q000601:surgery; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology / Q000637:transplantation; D055495:Neurogenesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050697:Retinal Dehydrogenase / Q000378:metabolism; D033581:Stem Cell Transplantation; D013997:Time Factors
chemical_list: D007527:Isoenzymes; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C523119:Aldh1a1 protein, rat; D050697:Retinal Dehydrogenase
keywords: Hippocampal neurogenesis; Multineurotrophin; Neural progenitor cell transplantation; Neuroprotection; Spatial memory; Traumatic brain injury