title: Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury.
abstract: We sought to evaluate the potential of C17.2 neural progenitor cells (NPCs) engineered to secrete glial cell line-derived neurotrophic factor (GDNF) to survive, differentiate and promote functional recovery following engraftment into the brains of adult male Sprague-Dawley rats subjected to lateral fluid percussion brain injury. First, we demonstrated continued cortical expression of GDNF receptor components (GFRalpha-1, c-Ret), suggesting that GDNF could have a physiological effect in the immediate post-traumatic period. Second, we demonstrated that GDNF over-expression reduced apoptotic NPC death in vitro. Finally, we demonstrated that GDNF over-expression improved survival, promoted neuronal differentiation of GDNF-NPCs at 6 weeks, as compared with untransduced (MT) C17.2 cells, following transplantation into the perilesional cortex of rats at 24 h post-injury, and that brain-injured animals receiving GDNF-C17.2 transplants showed improved learning compared with those receiving vehicle or MT-C17.2 cells. Our results suggest that transplantation of GDNF-expressing NPCs in the acute post-traumatic period promotes graft survival, migration, neuronal differentiation and improves cognitive outcome following traumatic brain injury.
authors.affiliation: Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Bakshi
authors.forename: Saori
authors.initials: S
authors.lastname: Shimizu
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Keck
authors.forename: Sean
authors.initials: S
authors.lastname: Cho
authors.forename: David G
authors.initials: DG
authors.lastname: LeBold
authors.forename: Diego
authors.initials: D
authors.lastname: Morales
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Snyder
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Watson
authors.forename: Tracy K
authors.initials: TK
authors.lastname: McIntosh
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000503:physiopathology / Q000601:surgery*; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D017690:Cell Transplantation / Q000379:methods*; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology / Q000601:surgery*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000627:therapeutic use*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D011930:Reaction Time / Q000502:physiology; D045442:Rotarod Performance Test / Q000379:methods; D013234:Stem Cells / Q000502:physiology*; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D049452:Green Fluorescent Proteins; D051096:Proto-Oncogene Proteins c-ret