title: Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent Notch signaling.
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.
authors: Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Manash K
authors: MK
authors: Paul
authors: Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Bharti
authors: B
authors: Bisht
authors: Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Daphne O
authors: DO
authors: Darmawan
authors: Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Richard
authors: R
authors: Chiou
authors: Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Vi L
authors: VL
authors: Ha
authors: Department of Pathology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: William D
authors: WD
authors: Wallace
authors: Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Andrew T
authors: AT
authors: Chon
authors: Division of Pulmonary Medicine, Department of Medicine, Keio University Medical School, Tokyo 160-8582, Japan.
authors: Ahmed E
authors: AE
authors: Hegab
authors: Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Tristan
authors: T
authors: Grogan
authors: 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.
authors: David A
authors: DA
authors: Elashoff
authors: Department of Pediatrics, Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Jackelyn A
authors: JA
authors: Alva-Ornelas
authors: 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.
authors: Brigitte N
authors: BN
authors: Gomperts
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D006706:Homeostasis; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D000077423:Polidocanol; D011092:Polyethylene Glycols / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D014132:Trachea / Q000166:cytology*; D014945:Wound Healing
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D051880:Receptors, Notch; D000077423:Polidocanol; D011092:Polyethylene Glycols