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To investigate the protective effects of HIF-1\u03b1-AA-modified BMSCs on neuron survival in cerebral ischemia models, we co-cultured HIF-1\u03b1-AA-modified BMSCs with neuron-like cells (PC12 cells) and observed a significant increase in the release of vascular endothelial growth factor (VEGF) from BMSCs, the decreased PC12 cell apoptosis, and the upregulation of Survivin expression reduced by hypoxia in PC12 cells compared to enhanced green fluorescent protein (EGFP) BMSCs. In addition, to explore whether VEGF secreted by HIF-1\u03b1-AA-modified BMSCs plays an important role in preventing hypoxia-induced apoptosis and the possible mechanism involved, exogenous VEGF were applied and the similar protective effects on PC12 cells were observed in vitro. Furthermore, hypoxia reduced the expression of phosphorylated Akt and phosphorylated FoxO1, whereas the administration of VEGF reversed these changes. Transfection of FoxO1 H215R, a DNA-binding mutant, abrogated the inhibitory ability on Survivin promoter activity, whereas FoxO1 AAA, the active form of FoxO1, presented further repression on Survivin promoter, indicating that FoxO1 directly binds on Survivin promoter as a transcriptional repressor and that phosphorylation status of FoxO1 affects its inhibition on the Survivin promoter. Transplantation of HIF-1\u03b1-AA-modified BMSCs after cerebral ischemia in vivo sufficiently reduced neurons apoptosis, decreased cerebral infarction volume, and induced a significant improvement on the modified neurological severity score compared to the EGFP BMSCs group. In conclusion, HIF-1\u03b1-AA-modified MSCs showed an obvious protective effect on neuron-like cells or neuron after ischemia in vitro and in vivo, at least in part, through the VEGF\/PI3K\/Akt\/FoxO1 pathway.<\/jats:p>","DOI":"10.1089\/scd.2011.0604","type":"journal-article","created":{"date-parts":[[2012,4,2]],"date-time":"2012-04-02T17:06:43Z","timestamp":1333386403000},"page":"2703-2717","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":42,"title":["Hypoxia-Inducible Factor 1-\u03b1-AA-Modified Bone Marrow Stem Cells Protect PC12 Cells from Hypoxia-Induced Apoptosis, Partially Through VEGF\/PI3K\/Akt\/FoxO1 Pathway"],"prefix":"10.1177","volume":"21","author":[{"given":"Qian","family":"Zhong","sequence":"first","affiliation":[{"name":"Sun Yat-Sen University","place":["China"]},{"name":"Sun Yat-sen University Cancer Center","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University","place":["China"]},{"name":"Guangdong Medical College","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibiao","family":"Ye","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuo","family":"Cai","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuquan","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Utah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Y.B.","family":"Deng","sequence":"additional","affiliation":[{"name":"Sun Yat-Sen University","place":["China"]},{"name":"Sun Yat-sen University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2012,4,2]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60694-7"},{"key":"e_1_3_3_3_2","unstructured":"The world health report 2004. 2004. 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