A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis.

Daoyuan Huang; Yuesheng Zuo; Chen Zhang; Guoqiang Sun; Ying Jing; Jinghui Lei; Shuai MA; Shuhui Sun; Huifen LU; Yusheng Cai; Weiqi Zhang; Fei Gao; Andy Peng Xiang; Juan Carlos Izpisua Belmonte; Guang-hui Liu; Jing QU; Si Wang

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A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis.

Author: Daoyuan HUANG ¹ ; Yuesheng ZUO ² ; Chen ZHANG ³ ; Guoqiang SUN ⁴ ; Ying JING ⁴ ; Jinghui LEI ¹ ; Shuai MA ⁵ ; Shuhui SUN ⁵ ; Huifen LU ¹ ; Yusheng CAI ⁵ ; Weiqi ZHANG ² ; Fei GAO ⁴ ; Andy PENG XIANG ⁶ ; Juan Carlos Izpisua BELMONTE ⁷ ; Guang-Hui LIU ¹ ; Jing QU ⁴ ; Si WANG ¹
Author Information

1. Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
2. University of Chinese Academy of Sciences, Beijing 100049, China.
3. The Fifth People's Hospital of Chongqing, Chongqing 400062, China.
4. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
5. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
6. Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 510000, China.
7. Altos Labs, Inc., San Diego, CA 92121, USA.
Publication Type:Journal Article
Keywords: WT1; aging; primate; single-nucleus RNA sequencing; testis
MeSH: Animals; Male; Testis; Sertoli Cells/metabolism*; Transcriptome; Spermatogenesis/genetics*; Primates; Aging/genetics*; Stem Cells
From: Protein & Cell 2023;14(12):888-907
CountryChina
Language:English
Abstract: The testis is pivotal for male reproduction, and its progressive functional decline in aging is associated with infertility. However, the regulatory mechanism underlying primate testicular aging remains largely elusive. Here, we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas. Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir, disturbed meiosis and impaired spermiogenesis along the sequential continuum. Remarkably, Sertoli cell was identified as the cell type most susceptible to aging, given its deeply perturbed age-associated transcriptional profiles. Concomitantly, downregulation of the transcription factor Wilms' Tumor 1 (WT1), essential for Sertoli cell homeostasis, was associated with accelerated cellular senescence, disrupted tight junctions, and a compromised cell identity signature, which altogether may help create a hostile microenvironment for spermatogenesis. Collectively, our study depicts in-depth transcriptomic traits of non-human primate (NHP) testicular aging at single-cell resolution, providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.