Effect of the PI3K/AKT signaling pathway on hypoxia-induced proliferation and differentiation of bone marrow-derived mesenchymal stem cells

Abstract

Bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation has been demonstrated to be an effective way of augmenting angiogenesis of ischemic tissue. The low oxygen conditions in ischemic tissue directly affect the biological behavior of engrafted cells. However, to date, the mechanism through which hypoxia regulates self-renewal, differentiation and paracrine function of BM-MSCs remains unclear. Clarification of this mechanism would be beneficial to the use of stem cell-based therapy. The PI3K/AKT pathway has been extensively investigated for its role in cell proliferation, cell transformation, paracrine function and angiogenesis. The present study aimed to analyze the role of PI3K/AKT pathway in hypoxia-induced proliferation of BM-MSCs and their differentiation into endothelial cells in vitro by the application of LY294002, a PI3K/AKT pathway inhibitor, with cells cultured in normoxia serving as a control. The results showed that rat BM-MSCs at passage 3 and 4 displayed only few phenotypical differences in the expression of surface antigens as detected by flow cytometry. When compared with the cells treated in normoxia, the proliferation of BM-MSCs in hypoxia was promoted, a greater number of cells expressed CD31 and a higher expression of vascular endothelial growth factor was observed after culture in hypoxic conditions. However, by inhibiting with LY294002, these changes induced by hypoxia were partly inhibited. In conclusion, the present study showed that the PI3K/AKT pathway served an important role in hypoxia-enhanced in vitro proliferation of BM-MSCs and their differentiation into endothelial cells and paracrine vascular endothelial growth factor.

Transforming Growth Factor β-Activated Kinase 1 Regulates Mesenchymal Stem Cell Proliferation Through Stabilization of Yap1/Taz Proteins

“…Inhibition of p38MAPK or Akt also affected BMMSC proliferation, although the suppressive effects of p38MAPK and Akt inhibition on cell proliferation were not critical. Consistently, previous studies have shown that MSCs can repopulate under suppression of ERK , p38MAPK , and Akt .…”

Strategies to retain properties of bone marrow–derived mesenchymal stem cellsex vivo

“…Several groups have demonstrated that the PI3K/AKT/mTOR and the PI3K/AKT/FOXO3a signaling pathways are associated with MSC survival in culture or animal models . It has also been demonstrated that activation of the PI3K/AKT signaling pathway is critical to increasing hypoxia‐induced proliferation and differentiation of MSCs into ECs …”

Low‐intensity pulsed ultrasound activates ERK1/2 and PI3K‐Akt signalling pathways and promotes the proliferation of human amnion‐derived mesenchymal stem cells

“…Phosphorylated Akt acts on the downstream target factors and plays a role in cell cycle regulation and cell growth. It has been reported that PI3K‐Akt pathway serves an important role in the proliferation of MSCs . However, whether ERK1/2 and PI3K/Akt signalling pathways are involved in the effect of LIPUS on proliferation of hAD‐MSCs are unknown.…”