posted on 2016-03-17, 14:12authored byAmir HossiniAmir Hossini, Annika Quast, Michael Plötz, Katharina Grauel, Tarik Exner, Judit Küchler, Harald Stachelscheid, Jürgen Eberle, Anja Rabien, Evgenia Makrantonaki, Christos Zouboulis
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.