Angiopoietin-1 protects mesenchymal stem cells against serum deprivation and hypoxia-induced apoptosis through the PI3KAkt pathway¹

Abstract

Aim: The angiopoietin-1 (Ang1)/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 cardiomyocytes. However, relatively little is known as to whether Ang1 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 staining 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 Western blot analysis. Results: This study showed that MSC expressed Tie-2 receptor, and Ang1 induced Tie-2 receptor phosphorylation. The protective effect of Ang1 on MSC was dose-dependent and peaked at 50 µg/L; however, the soluble Tie-2/Fc fusion protein, which acts as an inhibitor by sequestering Ang1, abrogated the anti-apoptotic effect. Ang1 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 Ang1 can protect MSC against serum deprivation and hypoxia-induced apoptosis; Ang1/Tie-2 signaling and its downstream PI3K/Akt messenger pathway are crucial in the processes leading to MSC survival.

Fibroblast Growth Factor-2 Enhances Proliferation and Delays Loss of Chondrogenic Potential in Human Adult Bone-Marrow-Derived Mesenchymal Stem Cells

“…The effects on MAPK signaling were not through elements of the feedback loop as previously reported, 18 but rather through the upstream regulators of MAPK signaling such as angiopoietin 1 and midkine, which are upregulated in cells with chondrogenic potential. These transcripts may have a role not only in the maintenance of the chondrogenic potential but also in the overall physiology of hMSCs; angiopoietin 1 has been implicated in the paracrine tissue repair activity displayed by MSCs [45][46][47] and as an antiapoptotic factor 48 ; secreted frizzledrelated protein 1 has also been reported to play a role in the tissue repair activity of MSCs 49,50 and in controlling osteogenic differentiation. [51][52][53] Additionally, a recent report indicates that six transmembrane epithelial antigen of the prostate 1, also upregulated in cells with chondrogenic potential, may be a marker for MSCs.…”

Lessons from Genetically Altered Mesenchymal Stem Cells (MSCs): Candidates for Improved MSC-Directed Myocardial Repair

“…Although these The MSC-secreted factors seem to have more than just proangiogenic effects; MSC treatment reduces the lacking (13). Instead of MSC-derived regeneration of the heart, researchers have shown a fusion event of apoptotic index within the peri-infarct area (37,68). In vitro, cultured cardiomyocytes have improved survival MSCs with injured cardiomyocytes (4).…”

Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways

“…It has also been demonstrated that preconditioning MSCs with stromal-derived factor 1α (SDF-1α) alone or in combination with growth factors such as fibroblast growth factor-2, insulin-like growth factor-1, and bone morphogenetic protein-2 can alleviate the host cell apoptosis and enhance their therapeutic effects (Mias et al, 2008). Our previous studies have shown that some candidates for preconditioning, such as heregulin (Mias et al, 2008), cyclosporin A (Chen et al, 2008), angiopoietin-1 (Liu et al, 2008), and dimethyloxalylglycine (DMOG) (Liu et al, 2009b), can protect MSCs against hypoxia and serum deprivation-induced apoptosis through classic cytoplasmic and/or mitochondrial apoptotic pathways.…”