A single-cell atlas of the testicular interstitium defines Leydig progenitor networks sustaining Leydig cell homeostasis across the lifespan
- Sun Yat-sen University, China
- Southern Medical University, China
- University of Louisville, United States
Abstract
Declining rates of male fertility pose a significant clinical challenge, while the mechanisms underlying testicular interstitial function remain incompletely understood. Here, we conducted a comprehensive analysis of the single-cell transcriptomic landscape of the murine testicular interstitium across the postnatal lifespan. The investigation unveiled a previously unrecognized population of Cd34+/Sox4+ mesenchymal cells nestled within the interstitium, hinting at their potential as Leydig cell progenitors. With the aging process of Cd34+/Sox4+ mesenchymal cells, we observed a decline in glutathione levels within the testicular interstitium. Remarkably, these Cd34+/Sox4+ mesenchymal cells exhibited clonogenic self-renewal capacity and a robust propensity to differentiate into Leydig cells. Intriguingly, when transplanted into Leydig cell-disrupted or failure models, Cd34+/Sox4+ cells efficiently colonized the testicular interstitium, resulting in a notable increase in testosterone production. Exploring the epigenetic landscape, we identified critical transcription factors, most notably Sox4, governing the stem cell fate of Cd34+/Sox4+ mesenchymal cells. Overall, this comprehensive lifespan-resolved single-cell atlas of testicular interstitial cells provides fundamental insights into Leydig cell progenitor biology and regenerative capacity during aging.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE262415 and GSE262416, once the article is accepted, the data will be made open access. All data generated or analysed during this study are included in the manuscript and supplemental information files. No new code have been generated for this manuscript, but can be provided separately if requested.
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Neonatal and adult human testis defined at the single-cell levelNCBI Gene Expression Omnibus, GSE124263.
Article and author information
Author details
Funding
National Natural Science Foundation of China (82172698)
- Wei Zhao
National Key Research and Development Program of China (2017YFA0103800)
- Wei Zhao
National Natural Science Foundation of China (82303201)
- Meiling Yang
High-level Hospital Construction Project of Guangdong Provincial People's Hospital (DFJHBF202102)
- Wei Zhao
National Key Research and Development Program of China (2023YFC2506100)
- Wei Zhao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals. All of the animals were handled according to 'Regulations on the management of experimental animals' and 'Guidelines on the good treatment of laboratory animals' of the Sun Yat-sen University. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Sun Yat-sen University (Permit Number: 2017-133). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Copyright
© 2025, Huang et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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A single-cell atlas of the testicular interstitium defines Leydig progenitor networks sustaining Leydig cell homeostasis across the lifespan
eLife 14:e100396.
https://doi.org/10.7554/eLife.100396
