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Neuroprotective Effects of Bone Marrow Stem Cells Overexpressing Glial Cell Line-Derived Neurotrophic Factor on Rats With Intracerebral Hemorrhage and Neurons Exposed to Hypoxia/Reoxygenation

Yang, Chaoxian MD*†; Zhou, Ling MD‡; Gao, Xiaoqing MD†; Chen, Bo MD†; Tu, Jiangyi MD†; Sun, Hengyun PhD§; Liu, Xiaoqing PhD∥; He, Jing MD¶; Liu, Juan MD¶; Yuan, Qionglan PhD¶#

doi: 10.1227/NEU.0b013e3182098a8a
Research-Human-Clinical Trials

BACKGROUND: Intracerebral hemorrhage (ICH) represents at least 15% of all strokes in the Western population and a considerably higher proportion at 50% to 60% in the Oriental population.

OBJECTIVE: To investigate whether administration of bone marrow stem cells (BMSCs) overexpressing glial cell line–derived neurotrophic factor (GDNF) provides more efficient neuroprotection for rats with ICH and neurons exposed to hypoxia/reoxygenation.

METHODS: Primary rat BMSCs were transfected with rat GDNF gene using virus vector (GDNF/BMSCs) and blank virus plasmid (BVP/BMSCs). Primary rat cortical neurons of rats were exposed to hypoxia and then reoxygenated with GDNF/BMSCs (GDNF/BMSCs group) or BVP/BMSCs (BMSCs group) treatment for 12 hours and 1, 2, 3, and 5 days. Hoechst 33258 staining was used to evaluate apoptosis. GDNF/BMSCs, BVP/BMSCs, and saline (GDNF/BMSCs, BMSCs, and control groups) were injected into the right striatum 3 days after rat ICH induced by injecting collagenase. Modified neurological severity scores and hematoxylin and eosin staining were performed to evaluate neurological function and lesion volume at 1 and 2 weeks after transplantation. Immunostaining was used to observe differentiation of grafted cells (neurofilament-200 for neurons, glial fibrillary acidic protein for astrocytes). The GDNF level and apoptosis were evaluated by Western blotting and terminal deoxynucleotidyl transferase dUTP nick-end labeling, respectively.

RESULTS: The GDNF/BMSCs group had significantly lowered apoptosis compared with the BMSCs group at the given time. The GDNF/BMSCs group had significantly improved functional deficits and reduced lesion volume compared with the BMSCs group. Stable GDNF expression in the GDNF/BMSCs group was detected at the given time in the host brain. The neurofilament-positive grafted cells in the GDNF/BMSCs group were more numerous than in the BMSCs group. The GDNF/BMSCs group had significantly decreased apoptotic cells compared with the BMSCs group.

CONCLUSION: These results suggest that GDNF/BMSCs provide better neuroprotection for rats with ICH and neurons exposed to hypoxia/reoxygenation.

*Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai, China; †Department of Neurobiology, Luzhou Medical College, Luzhou, China; ‡Department of Endocrine, Affiliated Hospital of Luzhou Medical College, Luzhou, China; §Department of Plastic and Reconstructive Surgery, 9th People′s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; ∥Stem Cell Research Center and Department of Regenerative Medicine, Tongji Eye Institute and ¶Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai, China; #State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China

Received, April 4, 2009.

Accepted, August 6, 2010.

Correspondence: Qionglan Yuan, PhD, Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai, 200092 China. E-mail: yqiongl@263.net

Copyright © by the Congress of Neurological Surgeons