A niche-dependent redox rheostat regulates epithelial stem cell fate
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.
Authors
- Meenakshi Rao (ORCID: https://orcid.org/0000-0002-8194-9204)
- Krishnan Raghunathan (ORCID: https://orcid.org/0000-0003-2228-6313)
- Anoohya N. Muppirala (ORCID: https://orcid.org/0000-0002-6810-4127)
- Michael Rutlin (ORCID: https://orcid.org/0009-0003-3657-1008)
- Jay R. Thiagarajah (ORCID: https://orcid.org/0000-0002-1437-325X)
- Unmesh Jadhav (ORCID: https://orcid.org/0000-0003-1102-1328)
- Elsy M. Ngwa (ORCID: https://orcid.org/0000-0002-0104-6700)
- Xu Zhou (ORCID: https://orcid.org/0000-0002-1692-6823)
- Stephen Babcock
- Daping Yang (ORCID: https://orcid.org/0000-0002-3104-1943)
- Daniel Kotlarz (ORCID: https://orcid.org/0000-0002-4576-6769)
- Eranthie Weerapana (ORCID: https://orcid.org/0000-0002-0835-8301)
- Bin Bao (ORCID: https://orcid.org/0000-0001-7610-3426)
- Zhongyang Wu
- C. H. Baek (ORCID: https://orcid.org/0000-0002-0644-365X)
- Scott B. Snapper (ORCID: https://orcid.org/0000-0003-0267-4247)
- George Ye (ORCID: https://orcid.org/0000-0003-1380-7121)
- José Ordovás-Montañés (ORCID: https://orcid.org/0000-0001-5444-5601)
- Mantu Bhaumik
- Xi Chen (ORCID: https://orcid.org/0000-0001-6394-9967)
- Andrew Kwong
- Qianni Peng
Institutions
- Boston College (US)
- Broad Institute (US)
- University of Southern California (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- Chinese Academy of Sciences (CN)
- Ragon Institute of MGH, MIT and Harvard (US)
- Helmholtz Zentrum München (DE)
- German Center for Pediatric and Adolescent Rheumatology (DE)
- Center for Excellence in Brain Science and Intelligence Technology (CN)
- Harvard Stem Cell Institute (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-66636-5
- Citations
- 1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94