Bakshi Asha, Shimizu Saori, Keck Carrie A, Cho Sean, LeBold David G, Morales Diego, Arenas Ernest, Snyder Evan Y, Watson Deborah J, McIntosh Tracy K
Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
Eur J Neurosci. 2006 Apr;23(8):2119-34. doi: 10.1111/j.1460-9568.2006.04743.x.
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.
我们试图评估经基因工程改造以分泌胶质细胞源性神经营养因子（GDNF）的C17.2神经祖细胞（NPCs）在植入遭受侧方液压冲击性脑损伤的成年雄性Sprague-Dawley大鼠脑内后存活、分化及促进功能恢复的潜力。首先，我们证实了GDNF受体组分（GFRalpha-1、c-Ret）在皮层持续表达，提示GDNF可能在创伤后即刻产生生理效应。其次，我们证明了GDNF过表达可减少体外凋亡的NPC死亡。最后，我们证明，与未转导的（MT）C17.2细胞相比，GDNF过表达可提高损伤后24小时移植入大鼠损伤周围皮层的GDNF-NPCs在6周时的存活率，促进其神经元分化，且接受GDNF-C17.2移植的脑损伤动物与接受载体或MT-C17.2细胞的动物相比，学习能力有所改善。我们的结果表明，在创伤后急性期移植表达GDNF的NPCs可促进移植物存活、迁移、神经元分化，并改善创伤性脑损伤后的认知结果。
