An interplay of NOX1-derived ROS and oxygen determines the spermatogonial stem cell self-renewal efficiency under
Hiroko Morimoto1, Takuya Yamamoto2,3,4,5, Takehiro Miyazaki1
1Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Genes & Development
|January 15, 2021
Summary
Oxygen levels critically impact spermatogonial stem cell (SSC) self-renewal. NADPH oxidase 1 (NOX1)-derived reactive oxygen species (ROS) are essential for SSC proliferation, especially under normoxia, influencing hypoxic responses.
Area of Science:
- Reproductive Biology
- Stem Cell Biology
- Cellular Physiology
Background:
- Spermatogonial stem cells (SSCs) self-renewal is linked to reactive oxygen species (ROS) produced by NADPH oxidase 1 (NOX1).
- The ROS-BCL6B-NOX1 pathway is implicated in feed-forward ROS production for SSC self-renewal.
- The influence of oxygen tension on this process remains incompletely understood.
Purpose of the Study:
- To investigate the critical role of oxygen tension on ROS-induced SSC self-renewal.
- To elucidate the specific contribution of NOX1-derived ROS versus mitochondria-derived ROS in SSC fate under varying oxygen conditions.
- To understand the interplay between NOX1, hypoxia-inducible factor 1-alpha (HIF1A), and CDKN1A in SSC proliferation.
Main Methods:
- Culture of SSCs under normoxic and hypoxic conditions.
- Assessment of SSC proliferation and BCL6B expression.
- Analysis of NOX1-derived and mitochondria-derived ROS.
- Gene deficiency studies (Nox1, Hif1a, Cdkn1a, Top1mt) in SSCs.
- In vivo analysis of undifferentiated spermatogonia in Nox1-deficient mice.
Main Results:
- SSCs proliferated poorly under hypoxia, with reduced BCL6B expression and diminished NOX1-derived ROS amplification.
- Nox1-deficient SSCs showed poor proliferation under hypoxia but normal proliferation under normoxia.
- NOX1-derived ROS influenced hypoxic responses in vivo, with Nox1 deficiency reducing HIF1A expression.
- Hypoxia-induced poor proliferation was rescued by Cdkn1a depletion, and Cdkn1a-deficient SSCs proliferated actively only under hypoxia.
- Mitochondria-derived ROS did not significantly influence SSC fate, highlighting the primary role of NOX1-derived ROS.
Conclusions:
- Oxygen tension is a critical regulator of SSC self-renewal, modulating ROS production and signaling pathways.
- NOX1-derived ROS are essential for SSC proliferation, particularly under normoxia, and influence hypoxic responses.
- The interplay between NOX1, HIF1A, and CDKN1A is crucial for SSC proliferation under different oxygen conditions, with CDKN1A acting as a key mediator of hypoxia-induced proliferation arrest.
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