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 1-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.

肠干细胞（Intestinal stem cells，ISCs）定位于具有区域异质性的微环境中，该微环境可提供多样的微环境信号，包括组织氧分压状态及形态发生素信号通路。目前学界对这些微环境信号与肠干细胞代谢及细胞命运的整合调控机制仍知之甚少。本研究证实，细胞氧化还原稳态可通过协调微环境因子与代谢状态，进而调控细胞命运决策。本研究发现，缺氧与Wnt信号通路（Wnt signaling）可协同作用，将活性氧生成酶NADPH氧化酶1（NADPH oxidase 1，NOX1）的分布区域限制性限定于远端结肠的隐窝基底。NOX1可维持氧化细胞状态，赋予细胞进入细胞周期的能力，进而改变肠干细胞不对称自我更新与谱系定向分化的平衡。从机制层面而言，细胞氧化还原状态可构建一条自我强化环路，将缺氧诱导因子1（hypoxia inducible factor 1）依赖的信号通路与代谢酶异柠檬酸脱氢酶1（isocitrate dehydrogenase 1）的翻译后调控相连接。本研究表明，氧化还原稳态充当细胞变阻器，是调控肠干细胞细胞周期代谢的核心且决定性因素。