title: 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.
authors.affiliation: Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.
authors.forename: Amir M
authors.initials: AM
authors.lastname: Hossini
authors.affiliation: Department of Dermatology and Allergy, Skin Cancer Center Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Annika S
authors.initials: AS
authors.lastname: Quast
authors.affiliation: Department of Dermatology and Allergy, Skin Cancer Center Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Plötz
authors.affiliation: NeuroCure Cluster of Excellence, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Department of Biology, Chemistry, Pharmacy, Institute of Biology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Grauel
authors.affiliation: Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.
authors.forename: Tarik
authors.initials: T
authors.lastname: Exner
authors.affiliation: Berlin Institute of Health-Stem Cell Core Facility, Berlin, Germany.
authors.forename: Judit
authors.initials: J
authors.lastname: Küchler
authors.affiliation: Berlin Institute of Health-Stem Cell Core Facility, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Stachelscheid
authors.affiliation: Department of Dermatology and Allergy, Skin Cancer Center Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eberle
authors.affiliation: Department of Urology and Berlin Institute of Urologic Research, Charité- Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Rabien
authors.affiliation: Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.|Research Geriatrics Group, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Department of Dermatology and Allergology, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Makrantonaki
authors.affiliation: Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany.
authors.forename: Christos C
authors.initials: CC
authors.lastname: Zouboulis
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D000077191:Wortmannin