Journal
THERANOSTICS
Volume 11, Issue 10, Pages 5010-5027Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.55645
Keywords
spermatogenesis; autophagy; single-cell RNA sequencing; spermatogonial stem cells; meiosis; male infertility
Categories
Funding
- National Key R&D Program of China [2016YFC1000606, 2017YFA0105001, 2019YFA0801802]
- National Natural Science Foundation of China [31671544, 81770104, 31970787, 81901542, 31601208, 82071711]
- Natural Science Foundation of Guangdong Province [2019A1515010784, 2019A1515010446, 2018030310294, 2017A030313098]
- Key Research & Development Program of Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) [2018GZR110104002]
- Science and Technology Projects of Guangzhou City [201904020031]
- Natural Science Foundation of Shenzhen [JCYJ20180305 163311448]
- Discipline Construction Funding of Shenzhen [2016-1452]
- SZU Top Ranking Project [86000000210]
- Beckman
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Autophagy plays a crucial role in spermatogenesis, with dysregulation of autophagy-related genes possibly contributing to male infertility. The study identified a unique global stage-specific enrichment of autophagy-related genes during human spermatogenesis and highlighted the importance of Cst3 in SSC maintenance and male germ cell development. The findings suggest a conservation of stage-specific expression pattern of autophagy-related genes in mammals and provide insights into potential therapeutic targets for male infertility.
Background: Autophagy has been implicated as a crucial component in spermatogenesis, and autophagy dysfunction can lead to reproductive disorders in animal models, including yeast, C. elegans and mice. However, the sophisticated transcriptional networks of autophagic genes throughout human spermatogenesis and their biological significance remain largely uncharacterized. Methods: We profiled the transcriptional signatures of autophagy-related genes during human spermatogenesis by assessing specimens from nine fertile controls (including two normal persons and seven obstructive azoospermia (OA) patients) and one nonobstructive azoospermia (NOA) patient using single-cell RNA sequencing (scRNA-seq) analysis. Dysregulation of autophagy was confirmed in two additional NOA patients by immunofluorescence staining. Gene knockdown was used to identify the role of Cst3 in autophagy during spermatogenesis. Results: Our data uncovered a unique, global stage-specific enrichment of autophagy-related genes. Human-mouse comparison analysis revealed that the stage-specific expression pattern of autophagy-related genes was highly conserved in mammals. More importantly, dysregulation of some clusters of autophagy-related genes was observed in NOA patients, suggesting the association of autophagy with male infertility. Cst3, a human-mouse conserved and autophagy-related gene that is actively expressed in spermatogonia and early spermatocytes, was found to regulate spermatogonial stem cell (SSC) maintenance and subsequent male germ cell development. Knockdown of Cst3 increased autophagic activity in mouse SSCs and subsequently suppressed the transcription of SSC core factors such as Oct4, Id1, and Nanos3, which could be efficiently rescued by manipulating autophagic activity. Conclusions: Our study provides comprehensive insights into the global transcriptional signatures of autophagy-related genes and confirms the importance of autophagy homeostasis in SSC maintenance and normal spermatogenesis, opening new avenues for further dissecting the significance of the autophagy regulatory network in spermatogenesis as well as male infertility.
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