Single-cell multiomics gene regulatory landscape reveals impaired spermatogonial stem cells and macrophage-driven inflammaging during testicular aging

Nanhe Lin; Zhiqiang Zhang; Xianshen Sha; Jiahui Yao; Xiangzhou Sun; Rui Sun; Jiajia Yang; Qiuhua Yu; Zhengfeng Wu; Jianfeng Guan; Chengqiang Mo; Bin Ouyang; Yun Xie

doi:10.1016/j.jgg.2026.05.005

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Single-cell multiomics gene regulatory landscape reveals impaired spermatogonial stem cells and macrophage-driven inflammaging during testicular aging

doi: 10.1016/j.jgg.2026.05.005

a. Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China;
b. Department of Andrology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518107, China;
c. Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, 55905, USA;
d. Department of Urology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China;
e. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China;
f. Department of Urology, Guizhou Hospital of The First Affiliated Hospital, Sun Yat-sen University, Guiyang, Guizhou 550025, China;
g. Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China;
h. Center for Reproductive Medicine, Guangdong Women and Children Hospital, Guangzhou, Guangdong 511400, China

Funds:

This work was supported by the National Natural Science Foundation of China (82401870, 82101819), Natural Science Foundation of Guangdong Province (2023A1515012310, 2023A1515012290, 2024A1515010094, 2024A1515010492), Guangzhou basic research planning for basic and applied basic research project (2025A04J4171), Fundamental Research Funds for the Central Universities, Sun Yat-sen University (24qnpy350), and Health Commission of Guizhou Province Scientific Research Project (gzwkj2025-058).

Received Date: 2025-12-18
Accepted Date: 2026-05-14
Rev Recd Date: 2026-05-13

Available Online: 2026-05-23

Abstract

Abstract

Testicular aging is a key driver of declining male reproductive health, but a comprehensive understanding of its underlying epigenetic drivers is lacking. To address this, we construct a multiomics aging atlas by integrating single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), and spatial transcriptomics of young and aged mouse testes. Our analysis reveals that altered chromatin accessibility accompanies transcriptional dysregulation and identifies spermatogonial stem cells (SSCs) as the most epigenetically vulnerable population. We further pinpoint ZFX as a consistently downregulated transcription factor in early germ cells, linking its decline to compromised SSC maintenance. In the somatic niche, we define disrupted regulatory networks that underpin impaired blood-testis barrier integrity in Sertoli cells and steroidogenic dysfunction in Leydig cells. Notably, we uncover an aberrant expansion of CD206⁺H2-Eb1^- macrophages that propagates local inflammation via the secreted factor CXCL13, which we demonstrate is sufficient to disrupt the SSC niche. Cross-species analysis identifies conserved aging-associated regulons, including BRCA1 and E2F1. This work provides a resource for understanding testicular senescence and nominates ZFX and CXCL13 as potential therapeutic targets for mitigating age-related reproductive decline.
- Testicular aging,
- Inflammaging,
- scATAC-seq,
- Spermatogonial stem cell,
- Macrophage

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