An interplay of NOX1-derived ROS and oxygen determines the spermatogonial stem cell self-renewal efficiency under hypoxia.
An interplay of NOX1-derived ROS and oxygen determines the spermatogonial stem cell self-renewal efficiency under hypoxia.
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DOI：
10.1101/gad.339903.120
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发表时间：
2021-02-01
影响因子：
10.5
通讯作者：
Shinohara T
中科院分区：
文献类型：
--
作者：
Morimoto H;Yamamoto T;Miyazaki T;Ogonuki N;Ogura A;Tanaka T;Kanatsu-Shinohara M;Yabe-Nishimura C;Zhang H;Pommier Y;Trumpp A;Shinohara T
在这项研究中，森本等人。试图研究精原干细胞（SSC）中活性氧（ROS）的调节方式。作者利用体内和基因组方法报告说，缺氧生态位决定了 SSC 中的 ROS 水平，而精子发生取决于 NOX1 和线粒体衍生的 ROS 之间的复杂平衡。 NADPH1 氧化酶 1 (NOX1) 产生的活性氧 (ROS) 被认为可通过 ROS-BCL6B-NOX1 途径前馈产生 ROS，从而驱动精原干细胞 (SSC) 自我更新。在这里，我们报告了氧对 ROS 诱导的自我更新的关键作用。尽管线粒体衍生的 ROS 增加，但在缺氧条件下培养的 SSC 增殖不良且缺乏 BCL6B 表达。由于缺氧条件下缺乏ROS扩增，NOX1衍生的ROS显着减少，并且Nox1缺陷的SSC在缺氧条件下增殖较差，但在常氧条件下增殖正常。 NOX1 衍生的 ROS 也会影响体内的缺氧反应，因为 Nox1 缺陷的未分化精原细胞表现出 HIF1A 的表达显着降低，HIF1A 是缺氧反应的主要转录因子。尽管 MYC 被激活并且 HIF1A 抑制了 CDKN1A，但缺氧导致的增殖不良仍然发生，而 HIF1A 的缺乏加剧了自我更新效率。 Cdkn1a 耗尽可以挽救缺氧条件下 Nox1 或 Hif1a 缺陷型 SSC 的增殖受损。与这些观察结果一致，Cdkn1a 缺陷的 SSC 仅在缺氧条件下活跃增殖，但在常氧条件下不活跃增殖。另一方面，对线粒体衍生的 ROS 或 Top1mt 线粒体特异性拓扑异构酶缺陷的化学抑制并不影响 SSC 的命运，这表明 NOX1 衍生的 ROS 在 SSC 中比线粒体衍生的 ROS 发挥更重要的作用。这些结果强调了 ROS 来源和氧张力对 SSC 自我更新的重要性。
In this study, Morimoto et al. sought to investigate how reactive oxygen species (ROS) are regulated in spermatogonial stem cells (SSCs). Using in vivo and genomic approaches, the authors report that hypoxic niche sets the ROS levels in SSCs, and spermatogenesis depends on an intricate balance between NOX1 and mitochondria-derived ROS. Reactive oxygen species (ROS) produced by NADPH1 oxidase 1 (NOX1) are thought to drive spermatogonial stem cell (SSC) self-renewal through feed-forward production of ROS by the ROS-BCL6B-NOX1 pathway. Here we report the critical role of oxygen on ROS-induced self-renewal. Cultured SSCs proliferated poorly and lacked BCL6B expression under hypoxia despite increase in mitochondria-derived ROS. Due to lack of ROS amplification under hypoxia, NOX1-derived ROS were significantly reduced, and Nox1-deficient SSCs proliferated poorly under hypoxia but normally under normoxia. NOX1-derived ROS also influenced hypoxic response in vivo because Nox1-deficient undifferentiated spermatogonia showed significantly reduced expression of HIF1A, a master transcription factor for hypoxic response. Hypoxia-induced poor proliferation occurred despite activation of MYC and suppression of CDKN1A by HIF1A, whose deficiency exacerbated self-renewal efficiency. Impaired proliferation of Nox1- or Hif1a-deficient SSCs under hypoxia was rescued by Cdkn1a depletion. Consistent with these observations, Cdkn1a-deficient SSCs proliferated actively only under hypoxia but not under normoxia. On the other hand, chemical suppression of mitochondria-derived ROS or Top1mt mitochondria-specific topoisomerase deficiency did not influence SSC fate, suggesting that NOX1-derived ROS play a more important role in SSCs than mitochondria-derived ROS. These results underscore the importance of ROS origin and oxygen tension on SSC self-renewal.
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