A niche-dependent redox rheostat regulates epithelial stem cell fate in the distal colon
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The intestinal epithelium is a rapidly regenerating tissue dependent on resident stem cell self-renewal and differentiation. The reactive oxygen species (ROS) generating enzyme NADPH oxidase 1 (NOX1) is spatially restricted to the crypt base epithelium in the distal colon. Using NOX1-deletion, along with cell-specific redox reporter mice, lineage tracing, single-cell transcriptomics, cysteine proteomics, and cell metabolic studies, we investigated the role of redox balance in colonic stem cell function. We show that distal colonic stem cells uniquely require NOX1-generated ROS to maintain a relatively oxidized state that promotes stem cell self-renewal. Mechanistically, this occurs through a cellular circuit that connects hypoxia inducible factor 1 (HIF1α)-dependent signaling to ROS regulation of isocitrate dehydrogenase 1 (IDH1), to maintain efficient cell cycle entry and cell fate determination in the relatively hypoxic distal colonic niche environment. Our studies therefore provide a basis for understanding regeneration dynamics and disease propensity in the distal large intestine.
GRAPHICAL ABSTRACT
HIGHLIGHTS
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The 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 H 2 O 2 both at homeostasis and during regeneration.
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Physiological increases in cellular H 2 O 2 favors maintenance of glycolysis in ISCs for self-renewal through regulation of isocitrate dehydrogenase 1 activity.
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Maintenance of the increased cellular oxidative state stabilizes HIF1α through a re-enforcing metabolic circuit.
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A 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.
