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bioRxiv · 10.1101/2025.01.26.634856

A niche-dependent redox rheostat regulates epithelial stem cell fate in the distal colon

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.·Jadhav, U.·Rao, M.·Weerapana, E.·Zhou, X.·Ordovas-Montanes, J.·Snapper, S. B.·Thiagarajah, J. R.
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Abstract

The niche environment surrounding intestinal stem cells (ISCs) varies along the length of intestine and provides key cues that regulate stem cell fate. Here, we investigated the role of cellular redox balance in colonic ISC function. We show that hypoxia and Wnt signaling synergize to restrict the reactive oxygen species (ROS) generating enzyme NADPH oxidase 1 (NOX1) to the crypt base in the distal colon. NOX1 function maintains a more oxidative cell state that licenses cell cycle entry, altering the balance of asymmetric stem cell self-renewal and directing lineage commitment. Mechanistically, cell redox state directs a self-reinforcing circuit that connects hypoxia inducible factor 1 (HIF1)-dependent signaling with regulation of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1). Our studies show that cellular redox balance is a central and niche-dependent regulator of epithelial homeostasis and regeneration and provide a basis for understanding disease propensity in the distal large intestine. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/634856v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@107798aorg.highwire.dtl.DTLVardef@1bc9013org.highwire.dtl.DTLVardef@96d56aorg.highwire.dtl.DTLVardef@95268d_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIThe balance of cycling intestinal stem cells (ISCs) versus committed epithelial cells in the uniquely hypoxic niche of the distal colon is regulated by NADPH oxidase 1 (NOX1) dependent H2O2 both at homeostasis and during regeneration. C_LIO_LIPhysiological increase in cellular H2O2 favors maintenance of glycolysis in ISCs for self-renewal through regulation of isocitrate dehydrogenase 1 activity. C_LIO_LIMaintenance of the increased cellular oxidative state stabilizes HIF1 through a re-enforcing metabolic circuit. C_LIO_LIA shift from a relatively oxidative to a reductive cell environment in distal colonic ISCs leads to decreased progression through the cell cycle and altered cell fate determination. C_LI

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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., Jadhav, U., Rao, M., Weerapana, E., Zhou, X., Ordovas-Montanes, J., Snapper, S. B., Thiagarajah, J. R.. 2025-01-28. A niche-dependent redox rheostat regulates epithelial stem cell fate in the distal colon. https://doi.org/10.1101/2025.01.26.634856

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