Dynamic Changes in Intracellular ROS Levels Regulate Airway Basal Stem Cell Homeostasis through Nrf2-Dependent Notch Signaling

Airways are exposed to myriad environmental and damaging agents such as reactive oxygen species (ROS), which also have physiological roles as signaling molecules that regulate stem cell function. However, the functional significance of both steady and dynamically changing ROS levels in different ste...

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Bibliographic Details
Published in:	Cell stem cell 2014-08, Vol.15 (2), p.199-214
Main Authors:	Paul, Manash K., Bisht, Bharti, Darmawan, Daphne O., Chiou, Richard, Ha, Vi L., Wallace, William D., Chon, Andrew T., Hegab, Ahmed E., Grogan, Tristan, Elashoff, David A., Alva-Ornelas, Jackelyn A., Gomperts, Brigitte N.
Format:	Article
Language:	eng
Subjects:	Animals Antioxidants - metabolism Cell Cycle Cell Differentiation Cell Proliferation Homeostasis Humans Mice NF-E2-Related Factor 2 - metabolism Oxidation-Reduction Polyethylene Glycols - chemistry Reactive Oxygen Species - metabolism Receptors, Notch - metabolism Signal Transduction Stem Cells - cytology Trachea - cytology Wound Healing
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Summary:	Airways are exposed to myriad environmental and damaging agents such as reactive oxygen species (ROS), which also have physiological roles as signaling molecules that regulate stem cell function. However, the functional significance of both steady and dynamically changing ROS levels in different stem cell populations, as well as downstream mechanisms that integrate ROS sensing into decisions regarding stem cell homeostasis, are unclear. Here, we show in mouse and human airway basal stem cells (ABSCs) that intracellular flux from low to moderate ROS levels is required for stem cell self-renewal and proliferation. Changing ROS levels activate Nrf2, which activates the Notch pathway to stimulate ABSC self-renewal and an antioxidant program that scavenges intracellular ROS, returning overall ROS levels to a low state to maintain homeostatic balance. This redox-mediated regulation of lung stem cell function has significant implications for stem cell biology, repair of lung injuries, and diseases such as cancer. [Display omitted] •ROS level flux regulates self-renewal of mouse and human airway basal stem cells•ROS flux signals through Nrf2 to regulate the canonical Notch pathway•Notch regulates airway basal stem cell self-renewal•Control of ROS flux by Nrf2 is critical for preserving airway stem cell homeostasis Paul et al. show that dynamic changes in the levels of reactive oxygen species activate Notch signaling to control proliferation and self-renewal of airway basal stem cells.
ISSN:	1934-5909 1875-9777