Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury.
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.
Bakshi
Asha
A
Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
Shimizu
Saori
S
Keck
Carrie A
CA
Cho
Sean
S
LeBold
David G
DG
Morales
Diego
D
Arenas
Ernest
E
Snyder
Evan Y
EY
Watson
Deborah J
DJ
McIntosh
Tracy K
TK
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
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