Adipose-derived mesenchymal stem cells protect PC12 cells from glutamate excitotoxicity-induced apoptosis by upregulation of XIAP through PI3-K/Akt activation.
Glutamate excitotoxicity has been implicated as one of the factors contributing to neuronal apoptosis and is involved in many neurodegenerative diseases. Previous studies suggest that mesenchymal stem cells have the ability to protect cultured neurons from excitotoxicity-induced apoptosis, although the underlying mechanisms are not clear. In this study, we evaluated whether adipose mesenchymal stem cells (AMSCs) could protect against glutamate-induced injury in PC12 cells by secreting neurotrophic factors. We found that AMSCs secreted neurotrophic factors including vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) under both normoxic and hypoxic conditions. AMSC - conditioned medium (AMSC-CM) had a protective effect on excitotoxicity-injured PC12 cells, as indicated by increased cell viability, decreased number of TUNEL-staining positive nuclei and lowered caspase-3 activity. By using neutralizing monoclonal antibodies and specific inhibitors, VEGF, HGF and BDNF were identified as the mediators of AMSC effects and PI3-K/Akt and MAPK pathways were involved. Western blot analysis showed that AMSC-CM can increase the level of p-Akt, up-regulate XIAP and reduce the level of cleaved-caspase-3 in PC12 cells. These results suggest that AMSCs can effectively protect PC12 cells from glutamate excitotoxicity-induced apoptosis and support the hypothesis that AMSCs may be a useful treatment for stroke or neurodegenerative diseases which often involve excitotoxicity.
Institute of Basic Medical Sciences & School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
Shan
S
Lu
Chunhua
C
Lu
Qin
Q
Han
Jing
J
Li
Zhijian
Z
Du
Lianming
L
Liao
Robert Chunhua
RC
Zhao
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism; D016716:PC12 Cells; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*
D009414:Nerve Growth Factors; D051636:X-Linked Inhibitor of Apoptosis Protein; D018698:Glutamic Acid; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3