A niche-dependent redox rheostat regulates epithelial stem cell fate

Year: 2025

Type: article

Abstract: 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. Intracellular redox state orchestrates a self-reinforcing circuit connecting hypoxia inducible factor 1α-dependent signalling with post-translational regulation of the metabolic enzyme isocitrate dehydrogenase 1 to govern intestinal stem cell fate.

Source: Nature Communications

DOI: 10.1038/s41467-025-66636-5

Authors: Xi Chen, Krishnan Raghunathan, Bin Bao, Elsy Ngwa, Andrew Kwong, Zhongyang Wu, Stephen Babcock, Clara Baek, George Ye, Anoohya Muppirala, Qianni Peng, Michael Rutlin, Mantu Bhaumik, Daping Yang, Daniel Kotlarz, Unmesh Jadhav, Meenakshi Rao, Eranthie Weerapana, Xu Zhou, Jose Ordovas-Montanes, Scott B. Snapper, Jay R. Thiagarajah

Institutions: Boston Children's Hospital, Harvard University, Broad Institute, Massachusetts Institute of Technology, Brigham and Women's Hospital, University of Southern California, USC Norris Comprehensive Cancer Center, Boston College, Chinese Academy of Sciences, Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Neuroscience, Helmholtz Munich, Ragon Institute of MGH, MIT and Harvard, Harvard Stem Cell Institute

Language: English

Topic: Redox biology and oxidative stress

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $6,990

Funders: U.S. Department of Health and Human Services, Pew Charitable Trusts, New York Stem Cell Foundation, Leona M. and Harry B. Helmsley Charitable Trust, Kenneth Rainin Foundation, G. Harold and Leila Y. Mathers Foundation, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development

OpenAlex ID: W4416785998