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PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells
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 signi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854383/ https://www.ncbi.nlm.nih.gov/pubmed/27138223 http://dx.doi.org/10.1371/journal.pone.0154770 |
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author | Hossini, Amir M. Quast, Annika S. Plötz, Michael Grauel, Katharina Exner, Tarik Küchler, Judit Stachelscheid, Harald Eberle, Jürgen Rabien, Anja Makrantonaki, Evgenia Zouboulis, Christos C. |
author_facet | Hossini, Amir M. Quast, Annika S. Plötz, Michael Grauel, Katharina Exner, Tarik Küchler, Judit Stachelscheid, Harald Eberle, Jürgen Rabien, Anja Makrantonaki, Evgenia Zouboulis, Christos C. |
author_sort | Hossini, Amir M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4854383 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-48543832016-05-07 PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells Hossini, Amir M. Quast, Annika S. Plötz, Michael Grauel, Katharina Exner, Tarik Küchler, Judit Stachelscheid, Harald Eberle, Jürgen Rabien, Anja Makrantonaki, Evgenia Zouboulis, Christos C. PLoS One Research Article 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. Public Library of Science 2016-05-03 /pmc/articles/PMC4854383/ /pubmed/27138223 http://dx.doi.org/10.1371/journal.pone.0154770 Text en © 2016 Hossini et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Hossini, Amir M. Quast, Annika S. Plötz, Michael Grauel, Katharina Exner, Tarik Küchler, Judit Stachelscheid, Harald Eberle, Jürgen Rabien, Anja Makrantonaki, Evgenia Zouboulis, Christos C. PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells |
title | PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells |
title_full | PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells |
title_fullStr | PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells |
title_full_unstemmed | PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells |
title_short | PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells |
title_sort | pi3k/akt signaling pathway is essential for survival of induced pluripotent stem cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854383/ https://www.ncbi.nlm.nih.gov/pubmed/27138223 http://dx.doi.org/10.1371/journal.pone.0154770 |
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