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Cell Stem Cell. 2014 Aug 7;15(2):199-214. doi: 10.1016/j.stem.2014.05.009. Epub 2014 Jun 19.

Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent Notch signaling.

Author information

1
Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2
Department of Pathology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3
Division of Pulmonary Medicine, Department of Medicine, Keio University Medical School, Tokyo 160-8582, Japan.
4
Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
5
Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Pulmonary Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6
Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA; Pulmonary Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: bgomperts@mednet.ucla.edu.

Abstract

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.

PMID:
24953182
PMCID:
PMC4127166
DOI:
10.1016/j.stem.2014.05.009
[Indexed for MEDLINE]
Free PMC Article

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