ROS Are Required for Mouse Spermatogonial Stem Cell Self-Renewal

• Published in: Cell stem cell Vol. 12; no. 6; pp. 774 - 786
• Main Authors: Morimoto, Hiroko, Iwata, Kazumi, Ogonuki, Narumi, Inoue, Kimiko, Atsuo, Ogura, Kanatsu-Shinohara, Mito, Morimoto, Takeshi, Yabe-Nishimura, Chihiro, Shinohara, Takashi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.06.2013
• Subjects: Adult Stem Cells - cytology; Adult Stem Cells - metabolism; Animals; Cell Proliferation; Cells, Cultured; fibroblast growth factor 2; hydrogen peroxide; Male; MAP Kinase Signaling System; Mice; Mice, Inbred Strains; mitogen-activated protein kinase; NAD(P)H oxidase (H2O2-forming); phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction; spermatogenesis; Spermatogonia - cytology; Spermatogonia - metabolism; stem cells; testes; tissues
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2013.04.001

Reactive oxygen species (ROS) generation is implicated in stem cell self-renewal in several tissues but is thought to be detrimental for spermatogenesis as well as spermatogonial stem cells (SSCs). Using cultured SSCs, we show that ROS are generated via the AKT and MEK signaling pathways under conditions where the growth factors glial cell line-derived neurotrophic factor and fibroblast growth factor 2 drive SSC self-renewal and, instead, stimulate self-renewal at physiological levels. SSCs depleted of ROS stopped proliferating, but they showed enhanced self-renewal when ROS levels were increased by the addition of hydrogen peroxide, which induced the phosphorylation of stress kinases p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK). Moreover, ROS depletion in vivo decreased SSC number in the testis, and NADPH oxidase 1 (Nox1)-deficient SSCs exhibited reduced self-renewal division upon serial transplantation. These results suggest that ROS generated by Nox1 play critical roles in SSC self-renewal via the activation of the p38 MAPK and JNK pathways. [Display omitted] •ROS are generated in spermatogonial stem cells (SSCs) by GDNF and FGF2•Increased ROS levels in SSCs enhance self-renewal division•Suppression of ROS by chemicals or Nox1 deficiency inhibits SSC self-renewal•ROS activate p38 MAPK and JNK, which are indispensable for SSC self-renewal Physiological levels of ROS are required for spermatogonial stem cell self-renewal.