The hypoxia-inducible factor EPAS1 is required for spermatogonial stem cell function in regenerative conditions
Ilana R. Bernstein,
Brett Nixon,
Jess M. Lyons,
Katerina B. Damyanova,
Camila S. De Oliveira,
Nishani S. Mabotuwana,
Simone J. Stanger,
Gerard E. Kaiko,
Tan Hui Ying,
Jon M. Oatley,
Nicole M. Skillen,
Alyssa J. Lochrin,
Jera L. Peters,
Tessa Lord
Affiliations
Ilana R. Bernstein
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Brett Nixon
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, Infertility and Reproduction Program, New Lambton Heights, NSW 2305, Australia
Jess M. Lyons
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Katerina B. Damyanova
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Camila S. De Oliveira
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Nishani S. Mabotuwana
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Simone J. Stanger
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Gerard E. Kaiko
Hunter Medical Research Institute, Immune Health Research Program, New Lambton Heights, NSW 2305, Australia; School of Biomedical Sciences and Pharmacy, College of Health and Medicine, The University of Newcastle, Callaghan, NSW 2308, Australia
Tan Hui Ying
Hunter Medical Research Institute, Immune Health Research Program, New Lambton Heights, NSW 2305, Australia; School of Biomedical Sciences and Pharmacy, College of Health and Medicine, The University of Newcastle, Callaghan, NSW 2308, Australia
Jon M. Oatley
School of Molecular Biosciences, Centre for Reproductive Biology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA
Nicole M. Skillen
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Alyssa J. Lochrin
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Jera L. Peters
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia
Tessa Lord
Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, Infertility and Reproduction Program, New Lambton Heights, NSW 2305, Australia; Corresponding author
Summary: In this study we explored the role of hypoxia and the hypoxia-inducible transcription factor EPAS1 in regulating spermatogonial stem cell (SSC) function in the mouse testis. We have demonstrated that SSCs reside in hypoxic microenvironments in the testis through utilization of the oxygen-sensing probe pimonidazole, and by confirming the stable presence of EPAS1, which is degraded at >5% O2. Through the generation of a germline-specific Epas1 knockout mouse line, and through modulation of EPAS1 levels in primary cultures of spermatogonia with the small drug molecule Daprodustat, we have demonstrated that EPAS1 is required for robust SSC function in regenerative conditions (post-transplantation and post-chemotherapy), via the regulation of key cellular processes such as metabolism. These findings shed light on the relationship between hypoxia and male fertility and will potentially facilitate optimization of in vitro culture conditions for infertility treatment pipelines using SSCs, such as those directed at pediatric cancer survivors.
