Thesis

Human pluripotent stem cells ameliorate NMDA-induced hippocampal degeneration and related functional deficits

Seizures, trauma and many neurologic diseases induce damage to the hippocampus, which can result in deficits in spatial navigation, memory consolidation and depressive-type behaviors. Current drug treatments have limited effectiveness in improving symptoms. Celavie Biosciences LLC has developed a human fetal brain-derived, pluripotent, nontumorigenic, hypoimmunogenic stem cell line with a normal karyotype (hfSC) that has previously shown an ability to migrate, differentiate and reduce structural and functional deficits in other neurodegenerative animal models. In this study, I examined if injected hfSCs into male Wistar rat CA3 hippocampal lesions will survive and possibly differentiate into mature pyramidal neurons, thereby diminishing neuronal damage. It has been established that the CA3 region of the hippocampus is involved in consolidating short-term memory to long-term memory and in spatial navigation. I stereotactically lesioned the CA3 regions at 50 days bilaterally with the neurotoxin NMDA (1μl containing 7.5 mg/ml; -3.5 mm AP; ±2.0 L and -2.5 V). At 54 days of age, live hfSC (500,000 cells in 5μl cell suspension media) for our treatment group, frozen-killed hfSC (500,000 cells/ 5μl), HEK293T cells (500,000 cells/5μl), or cell suspension media (5μl) were bilaterally implanted directly into the NMDA damaged area. The rats were tested two weeks later (68 days) with various memory tests, including the water-maze task, and novel and place-object tests. My results showed that rats receiving live hfSC implantation performed significantly better in the water maze task than control groups. Novel and place object tests showed no significant differences among the treatment groups. Histology confirmed the survival of implanted hfSCs up to 28 days post-implantation. My study has shown that Celavie's human derived pluripotent stem cells were able to survive in vivo and improve hippocampal functionality, highlighting the potential promise for stem cell treatment of brain damage in neurodegenerative diseases.

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