Transplantation of neural stem cells overexpressing glial cell line-derived neurotrophic factor enhances Akt and Erk1/2 signaling and neurogenesis in rats after stroke

• Published in: Chinese medical journal 2013-04, Vol.126 (7), p.1302-1309
• Main Authors: Yuan, Miao, Wen, Sheng-Jun, Yang, Chao-Xian, Pang, Yuan-Guang, Gao, Xiao-Qing, Liu, Xiao-Qing, Huang, Liang, Yuan, Qiong-Lan
• Format: Article
• Language: English
• Subjects: Animals; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Male; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurogenesis - physiology; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Stem Cell Transplantation; Stroke - metabolism; Stroke - therapy
• ISSN: 0366-6999
• DOI: 10.3760/cma.j.issn.0366-6999.20122965

Our previous studies have indicated that the beneficial effects of grafting neural stem cells (NSCs) overexpressing glial cell line-derived neurotrophic factor (GDNF) in rats after stroke. However, the underlying mechanisms are highly debatable. In this study, we investigated whether neurogenesis, Akt, and extracellular signal-regulated kinase 1/2 (Erk1/2) signaling were involved in this process. Transient ischemic stroke were induced by occluding middle cerebral artery for 2 hours and reperfusion. At 3 days after reperfusion, GDNF/NSCs, NSCs, and vehicle were administered. Immunohistochemical staining was used to evaluate neurogenesis by nestin antibody; phosphorylation of Akt and Erk1/2 was investigated by Western blotting analysis. Transplantation of GDNF/NSCs and NSCs significantly increased nestin-positive cells compared to control group (vehicle) from 1 to 7 weeks after reperfusion, and GDNF/NSCs showed stronger effect than NSCs at 2 and 3 weeks after reperfusion. Meanwhile, enhanced phosphorylation level of Erk1/2 was observed in the GDNF/NSCs and NSCs groups compared with control group, and phosphorylation level of Erk1/2 in GDNF/NSCs group was remarkably higher than that of NSCs group at any given time. In contrast, expression of mitogen-activated protein kinase phosphatase-1 (MKP-1), known as inhibitor of Erk1/2 signaling, was significantly decreased in the GDNF/NSCs and NSCs groups compared with the control group. Moreover, much enhanced and prolonged phosphorylation level of Akt of GDNF/NSCs group was detected compared with control and NSCs group. Grafting GDNF/NSCs enhances neurogenesis and activates Akt and Erk1/2 signaling, that may provide the potential for GDNF/NSCs in stroke treatment.