Aim: The angiopoietin-1 (Ang 1)/Tie-2 signaling system not only plays a pivotal role in vessel growth, remodeling, and maturation, but also reduces apoptosis of endothelial cells, neurons, and cardiomyoeytes. However, relatively little is known as to whether Angl has a protective effect on mesenchymal stem cells (MSC). The aim of the present study was to investigate the protective effect of Ang1/Tie-2 signaling on MSC against serum deprivation and hypoxia-induced apoptosis, and to determine the possible mechanisms. Methods: Hoechst 33342 and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling stain-ing were used to assess the apoptosis of MSC. The expression of Tie-2, Akt, Bcl-2, Bax, and cleaved caspase-9 and -3 was detected by Weste blot analysis. Results: This study showed that MSC expressed Tie-2 receptor, and Angl induced Tie-2 receptor phosphorylation. The protective effect of Angl on MSC was dose-depen-dent and peaked at 50 μg/L; however, the soluble Tie-2/Fc fusion protein, which acts as an inhibitor by sequestering Angl, abrogated the anti-apoptotic effect. Angl induced Akt phosphorylation, increased the Bcl-2/Bax ratio, and decreased the activation of caspase-9 and -3. All these effects were attenuated by Tie-2/Fc and a phosphatidylinositol 3 kinase (PI3K) inhibitor, wortmannin. Conclusion: These results demonstrate that Ang 1 can protect MSC against serum deprivation and hypoxia-induced apoptosis; Angl/Tie-2 signaling and its downstream PI3K/Akt messenger pathway are crucial in the processes leading to MSC survival.