Neuroprotective and behavioral efficacy of nerve growth factor-transfectedhippocampal progenitor cell transplants after experimental traumatic braininjury

Object. Immortalized neural progenitor cells derived from embryonic rat hip pocampus (HiB5), were transduced ex vivo with the gene for mouse nerve grow th factor (NGF) to secrete NGF (NGF-HiB5) at 2 ng/hr/10(5) cells in culture . Methods. Fifty-nine male Wistar rats weighing 300 to 370 g each were anesth etized with 60 mg/kg sodium pentobarbital and subjected to lateral fluid-pe rcussion brain injury of moderate severity (2.3-2.4 atm, 34 rats) or sham i njury (25 rats). At 24 hours postinjury, 2 mul (150,000 cells/mul) of [H-3] thymidine-labeled NGF-HiB5 cells were transplanted stereotactically into th ree individual sites in the cerebral cortex adjacent to the injury site (14 rats). Separate groups of brain-injured rats received nontransfected (naiv e [n])-HiB5 cells (12 animals) or cell suspension vehicle (eight animals). One week postinjury, animals underwent neurological evaluation for motor fu nction and cognition (Morris water maze) and were killed for histological, autoradiographic, and immunocytochemical analysis. Viable HiB5 cell grafts were identified in all animals, together with reactive microglia and macrop hages located throughout the periinjured parenchyma and grafts (OX-42 immun ohistochemistry). Brain-injured animals transplanted with either NGF-HiB5 o r n-HiB5 cells displayed significantly improved neuromotor function (p < 0. 05) and spatial learning behavior (p < 0.005) compared with brain-injured a nimals receiving microinjections of vehicle alone. A significant reduction in hippocampal CA3 cell death was observed in brain-injured animals receivi ng transplants of NGF-HiB5 cells compared with those receiving n-HiB5 cells or vehicle (p < 0.025). Conclusions. This study demonstrates that immortalized neural stem cells th at have been retrovirally transduced to produce NGF can markedly improve co gnitive and neuromotor function and rescue hippocampal CA3 neurons when tra nsplanted into the injured brain during the acute posttraumatic period.