The PI3K/Akt/mTOR pathway mediates retinal progenitor cell survival under hypoxic and superoxide stress.
| Title: | The PI3K/Akt/mTOR pathway mediates retinal progenitor cell survival under hypoxic and superoxide stress. |
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| Authors: | Sanghera KP; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada.; Mathalone N; Baigi R; Panov E; Wang D; Zhao X; Hsu H; Wang H; Tropepe V; Ward M; Boyd SR |
| Source: | Molecular and cellular neurosciences [Mol Cell Neurosci] 2011 Jun; Vol. 47 (2), pp. 145-53. Date of Electronic Publication: 2011 Apr 02. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Academic Press Country of Publication: United States NLM ID: 9100095 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9327 (Electronic) Linking ISSN: 10447431 NLM ISO Abbreviation: Mol Cell Neurosci Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: San Diego : Academic Press, c1990- |
| MeSH Terms: | Cell Hypoxia/*physiology ; Cell Survival/*physiology ; Phosphatidylinositol 3-Kinases/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Retina/*cytology ; Stem Cells/*physiology ; Superoxides/*metabolism ; TOR Serine-Threonine Kinases/*metabolism; Erythropoietin/metabolism ; Erythropoietin/pharmacology ; Hydrogen Peroxide/pharmacology ; Insulin/metabolism ; Oxidants/pharmacology ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Stem Cells/cytology ; Stem Cells/drug effects ; Animals ; Cells, Cultured ; Mice ; Phosphorylation ; Stress, Physiological |
| Abstract: | Oxygen (O₂) tension has emerged as a major regulator of stem cell (SC) biology. Low O₂ concentrations that are toxic to mature cells can confer advantage to stem and early progenitors, while superoxide stress remains a constant threat in aerobic biology and may be partially avoided through sequestration of SCs in the relatively hypoxic stem or regenerative niche. Using primary retina-derived retinal progenitor cells (RPCs) and the R28 progenitor cell line in vitro, we show that RPCs are sensitive to hydrogen peroxide (H₂O₂) induced damage and resistant to moderate levels of low oxygen stress (1% O₂). Under hypoxic conditions, multipotent RPCs upregulate Epo receptors, and Epo, along with insulin, protects against both superoxide- and severe hypoxia- (0.25% O₂) induced apoptosis through activation of the canonical PI3K/Akt/mTOR pathway. This survival advantage is sensitive to inhibitors of PI3K and mTOR. We further demonstrate phosphorylation of the p70S6 ribosomal kinase, a downstream mediator of PI3K/Akt/mTOR and translational activator. Overall, these data confirm that RPCs are sensitive to superoxide stress and resistant to hypoxia and that this resistance is mediated in part by Epo. They further suggest that manipulation of RPCs ex vivo prior to ocular delivery, or the in vivo delivery of exogenous survival factors at the time of cell implantation, could enhance the success of regenerative therapies aimed to restore sight.; (Copyright © 2011 Elsevier Inc. All rights reserved.) |
| Grant Information: | CPG-83460 Canada Canadian Institutes of Health Research |
| Substance Nomenclature: | 11096-26-7 (Erythropoietin); BBX060AN9V (Hydrogen Peroxide); 0 (Insulin); 0 (Oxidants); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); 11062-77-4 (Superoxides); EC 2.7.11.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (MTOR protein, human) |
| Entry Date(s): | Date Created: 20110406 Date Completed: 20111003 Latest Revision: 20260128 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.mcn.2011.03.010 |
| PMID: | 21463685 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't