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Chen, X.* ; Raghunathan, K.* ; Bao, B.* ; Ngwa, E.* ; Kwong, A.* ; Wu, Z.* ; Babcock, S.* ; Baek, C.* ; Ye, G.* ; Muppirala, A.* ; Peng, Q.* ; Rutlin, M.* ; Bhaumik, M.* ; Yang, D.* ; Kotlarz, D.M. ; Jadhav, U.* ; Rao, M.* ; Weerapana, E.* ; Zhou, X.* ; Ordovas-Montanes, J.* ; Snapper, S.B.* ; Thiagarajah, J.R.*

A niche-dependent redox rheostat regulates epithelial stem cell fate.

Nat. Commun. 16:11713 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Intestinal stem cells (ISCs) reside in regionally variable niches that provide diverse microenvironmental cues such as tissue oxygen status, and morphogen signaling. Integration of these cues with ISC metabolism and fate remains poorly understood. Here, we show that cellular redox balance orchestrates niche factors with metabolic state to govern cell fate decisions. We demonstrate that hypoxia and Wnt signaling synergistically restrict the reactive oxygen species generating enzyme NADPH oxidase 1 (NOX1) regionally to the crypt base in the distal colon. NOX1 enables maintenance of an oxidative cell state that licenses cell cycle entry, altering the balance of asymmetric ISC self-renewal and lineage commitment. Mechanistically, cell redox state directs a self-reinforcing circuit that connects hypoxia inducible factor 1α-dependent signaling with post-translational regulation of the metabolic enzyme isocitrate dehydrogenase 1. Our studies show redox balance acts as a cellular rheostat that is central and causative for metabolic control of the ISC cell-cycle.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Hypoxia-inducible Factors; Metabolic-regulation; Small-intestine; Colonic Crypt; Self-renewal; Homeostasis; Oxidation; Differentiation; Cancer; Nox1
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 16, Heft: 1, Seiten: , Artikelnummer: 11713 Supplement: ,
Verlag Springer
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Translational Genomics (ITG)
Förderungen Kenneth Rainin Foundation (Rainin Foundation)
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
Pew Charitable Trusts
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
New York Stem Cell Foundation (NYSCF)
U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)
G. Harold and Leila Y. Mathers Foundation (G. Harold & Leila Y. Mathers Foundation)
Leona M. and Harry B. Helmsley Charitable Trust (Helmsley Charitable Trust)