PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells

Abstract

Apoptosis is a highly conserved biochemical mechanism which is tightly controlled in cells. It contributes to maintenance of tissue homeostasis and normally eliminates highly proliferative cells with malignant properties. Induced pluripotent stem cells (iPSCs) have recently been described with significant functional and morphological similarities to embryonic stem cells. Human iPSCs are of great hope for regenerative medicine due to their broad potential to differentiate into specialized cell types in culture. They may be useful for exploring disease mechanisms and may provide the basis for future cell-based replacement therapies. However, there is only poor insight into iPSCs cell signaling as the regulation of apoptosis. In this study, we focused our attention on the apoptotic response of Alzheimer fibroblast-derived iPSCs and two other Alzheimer free iPSCs to five biologically relevant kinase inhibitors as well as to the death ligand TRAIL. To our knowledge, we are the first to report that the relatively high basal apoptotic rate of iPSCs is strongly suppressed by the pancaspase inhibitor QVD-Oph, thus underlining the dependency on proapoptotic caspase cascades. Furthermore, wortmannin, an inhibitor of phosphoinositid-3 kinase / Akt signaling (PI3K-AKT), dramatically and rapidly induced apoptosis in iPSCs. In contrast, parental fibroblasts as well as iPSC-derived neuronal cells were not responsive. The resulting condensation and fragmentation of DNA and decrease of the membrane potential are typical features of apoptosis. Comparable effects were observed with an AKT inhibitor (MK-2206). Wortmannin resulted in disappearance of phosphorylated AKT and activation of the main effector caspase-3 in iPSCs. These results clearly demonstrate for the first time that PI3K-AKT represents a highly essential survival signaling pathway in iPSCs. The findings provide improved understanding on the underlying mechanisms of apoptosis regulation in iPSCs.

Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells

“…The upregulation of the PI3K/Akt signaling has been associated with increased stem cell survival (Hossini et al, 2016). …”

Mitochondrial stress and activation of PI3K and Akt survival pathway in bladder ischemia

“…These cellular responses to ischemia may play a role in cell survival signaling via PI3K/Akt pathway to promote function and preserve subcellular structures. The PI3K/Akt signaling pathway plays a critical role in cell danger signals in a wide range of cellular stress conditions including ischemia and redox 21,22. Activation of PI3K/Akt pathway is a signal transduction that promotes survival and growth in response to integrating stress signals through the stress sensors 21,22.…”

“…The PI3K/Akt signaling pathway plays a critical role in cell danger signals in a wide range of cellular stress conditions including ischemia and redox 21,22. Activation of PI3K/Akt pathway is a signal transduction that promotes survival and growth in response to integrating stress signals through the stress sensors 21,22. Survival signaling via PI3K/Akt pathway can be activated exogenously by growth factors and cytokines and endogenously by the constitutively active regulatory proteins 21,22.…”

Gambogic acid prevents angiotensin II‑induced abdominal aortic aneurysm through inflammatory and oxidative stress dependent targeting the PI3K/Akt/mTOR and NF‑κB signaling pathways

“…The extracellular matrix, including elastic fibers, collagen, laminin and fibronectin, can be degraded through the cutting and activation of N2 end by enzyme, and has been recognized to serve a very important role in the incidence and development of aortic aneurysm (28). Most members of the MMP family serve important role in this process, in which MMP-2 and MMP-9 are especially important (29). Studies on arterial medial smooth muscle cells have demonstrated that normal arterial smooth muscle cells are the main components of artery intima media, which are not only associated with the diastolic and systolic function of arterial walls, but also regulate the synthesis and repair of extracellular matrix components, such as elastins and collagens (27,29).…”