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Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism

Nature Aging (2024)Cite this article

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Abstract

Age-related changes in testicular function can impact health and well-being. The mechanisms underlying age-related testicular dysfunction, such as late-onset hypogonadism (LOH), remain incompletely understood. Using single-cell RNA sequencing on human testes with LOH, we delineated Sertoli cells (SCs) as pivotal metabolic coordinators within the testicular microenvironment. In particular, lysosomal acidity probing revealed compromised degradative capacity in aged SCs, hindering autophagy and phagocytic flux. Consequently, SCs accumulated metabolites, including cholesterol, and have increased inflammatory gene expression; thus, we termed these cells as phago-/auto-lysosomal deregulated SCs. Exposure to a high-fat diet-induced phago-/auto-lysosomal dysregulated-like SCs, recapitulating LOH features in mice. Notably, efferent ductular injection and systemic TRPML1 agonist administration restored lysosomal function, normalizing testosterone deficiency and associated abnormalities in high-fat diet-induced LOH mice. Our findings underscore the central role of SCs in testis aging, presenting a promising therapeutic avenue for LOH.

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Fig. 1: SC aging in individuals with LOH revealed by scRNA transcriptome analysis.
Fig. 2: SCs in individuals with LOH were overwhelmingly phagocytic with dysregulated lysosomal acidity.
Fig. 3: Low degradation efficiency of PALD SCs.
Fig. 4: HFD stress accelerated the emergence of PALD-like SCs and the LOH phenotypes.
Fig. 5: TRPML agonist ML-SA1 restores lysosomal function in PALD SCs.
Fig. 6: EDI treatment of ML-SA1 ameliorated the HFD-induced LOH-like phenotype in mice.
Fig. 7: Systemic administration of ML-SA1 ameliorates HFD-LOH without adverse effects on spermatogenesis by TRT.

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Data availability

scRNA-seq data of this study can be found in the NCBI under accession numbers GSE149512 and GSE215754. Bulk RNA-seq data used in this study is available in the NCBI under accession number GSE218384. Source data are provided with this paper.

Code availability

All code associated with this paper and the gene annotation list have been uploaded to GitHub (https://github.com/zlyingithub/human-testis-aging-atlas)55.

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Acknowledgements

We express our gratitude to H.M. Wang (Institute of Zoology, CAS), L.S. Li (Shanghai Advanced Research Institute, CAS), and X.C. Wang (Institute of Biophysics, CAS) for their valuable comments and constructive input. We especially thank the Molecular Imaging Core Facility (MICF), Molecular and Cell Biology Core Facility (MCBCF) and the Multi-Omics Core Facility (MOCF) of the School of Life Science and Technology, ShanghaiTech University, for providing essential technical support. This work received support from grants provided by the Ministry of Science and Technology (MOST) (2018YFA0107702 and 2022YFC2702700) and the National Natural Science Foundation of China (NSFC; 32270896, 31771650 and 82201756). Additional funding was received from the ShanghaiTech startup, and the Shanghai Clinical Research and Trial Center.

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Author notes

  1. These authors contributed equally: Zhiwen Deng, Liangyu Zhao, Sha Li.

Authors and Affiliations

  1. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Zhiwen Deng, Liangyu Zhao, Sha Li, Xiaoyang Chen, Xiaohan Ling, Jiajun Zheng, Kunkun Yu, Jing Xu, Jiayi Liang, Huimin Feng, Lanlan Wu & Zhi Zhou

  2. Shanghai Clinical Research and Trial Center, Shanghai, China

    Zhiwen Deng, Sha Li, Xiaoyang Chen, Xiaohan Ling, Jiajun Zheng, Kunkun Yu & Zhi Zhou

  3. Department of Andrology, the Center for Men’s Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Liangyu Zhao, Chencheng Yao, Sha Han, Peng Li, Ruhui Tian, Tao Jing & Zheng Li

  4. Department of Urology, Department of Interventional Medicine, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China

    Liangyu Zhao, Yuxin Tang, Yingbo Dai & Minbo Yan

  5. Department of Andrology, the Affiliated Hospital of Qingdao University, Qingdao, China

    Tao Jing

  6. Shanghai Advanced Research Institute, Stem Cell and Reproductive Biology Laboratory, Chinese Academy of Sciences, Shanghai, China

    Chenchen Wang

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Contributions

Z.Z., Z.L. and C.W. conceptualized this project and supervised the overall experiments. Z.D., L.Z., S.L., X.C., J.Z., K.Y., J.X., X.L., H.F., L.W. and J.L. performed experiments. L.Z., Z.D. and S.L conducted data analysis. C.Y., S.H., P.L., R.T., T.J., Y.T., Y.D. and M.Y. conducted clinical data analysis.

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Correspondence to Chenchen Wang, Zheng Li or Zhi Zhou.

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Extended data

Extended Data Fig. 1 Evaluation of testicular degeneration in LOH patients.

a, b, Description of C/C scoreand DAPI staining showed how C/C scores were calculated(a), C/C score of three representative patients were quantified(b). c, Schematic diagram of the workflow in this study. d, Information about the sample donor (see also Supplementary Table 1). e, UMAP plot showed the 9 clusters of testicular cells, which were further grouped in somatic cell and germ cell clusters. f, UMAP plots of germ cells from young, healthy aged and LOH. g, GO categories of genes enriched in each cell type from the testis of young donors compared with LOH donors. h, Babble diagram showing the dissimilarity of SASP gene sets between somatic cell clusters of Young, HA and LOH patients. i, GO categories of DEGs enriched in SCs. j, Babble diagram showing genes of steroid biosynthetic process in SCs. Comparison by two-tailed unpaired t-test. Scale bars: 100 μm (a).

Source data

Extended Data Fig. 2 Primary SCs form young donors and LOH patients.

a, b, Flowchart overview of primary SC isolation, identification, and culture (nSC_Y = 16 ROI, nSC_LOH = 13). c, d, Representative image and quantification showing autophagic flux blockade in the SCLOH samples (nSC_Y, SC_LOH = 15 ROI).e, The flow cytometry pattern of SC with mRFP-eGFP-LC3 transgene. f, The flow cytometry of green fluorescence intensity of mRFP-eGFP-LC3 SC between Y and LOH. Three individual patients for each group (d). The cells were derived from two individual patients for each group (b). Data are presented as mean ± s.e.m. Comparison by two-tailed unpaired t-test. Scale bars: 10 μm (b, c).

Source data

Extended Data Fig. 3 Senescence of PALD SCs after phagocytosis.

a, Diagram of phagocytosis induction in Sertoli cells. b, IPA analysis between the SCLOH before and after phagocytosis induction. c, Volcano plot showing cytokine secretion from IPA analysis. d, β-gal staining of LCs from a (nSC_Y, SC_LOH = 6 ROI). The cells were derived from two individual patients for each group. Data are presented as mean ± s.e.m. Comparison by two-tailed unpaired t-test. Scale bars: 10 μm (d).

Source data

Extended Data Fig. 4 HFD-LOH mice modeling.

a, FACS profile showing unacidified lysosomes accumulated in the SC treated with Baf A for 12 h by LysoSensor probe. b, Body weight of mice with normal or high fat diet for 10 months. c, Ratio of testis weight to Body weight in ND or HFD-LOH mice (nND, HFD-LOH = 12 mice). d, Representative staining and quantification of VASA+ cell indicating atrophy of seminiferous tubules (nND, HFD-LOH = 20 ROI). e, Representative images of PPT1 level in SCs of ND or HFD-LOH mice(nND = 376 cells, nHFD-LOH = 345). f, Diagram and records of Rotarod assay in ND or HFD-LOH mice (nND, HFD-LOH = 8 mice). g, h, Schematic diagram showing the sexual behavior (g) including sniffing and mating (h) in ND or HFD-LOH mice (nND, HFD-LOH = 6 mice). At least five individual mice for each group. The boxes represent the median and interquartile range and the bars represent roughly 95% confidence interval for comparing medians (e). Data are presented as mean ± s.e.m (c, d, f, h). Comparison by two-tailed unpaired t-test. Scale bars: 50 μm (d, e).

Source data

Extended Data Fig. 5 Targeting and enhancing degradative capacity of PALD SCs.

a–c, GO and IPA analysis of major regulator in PALD SCs in young and LOH patients treated with/without MLSA1. d, Time lapse diagram of cholesterol and lysosome in PALD SCs with or without ML-SA1 treatment. e, DEGs of Cholesterol and testosterone synthesis in Leydig cells. Scale bars: 2 μm (f).

Extended Data Fig. 6 Systemic administration of ML-SA1 in HFD-LOH mice.

a, Body weight of HFD-LOH mice with daily ML-SA1 treatment and TRT (nVehicle, ML-SA1 = 6 mice, nTestosterone = 5). b, Representative mouse testis and the ratio of testis weight to body weight in HFD-LOH mice with ML-SA1 treatment and TRT (nVehicle, ML-SA1 = 12, nTestosterone = 10). c, d, Representative staining and quantification of PPT1(c) and NileRed (d) in testis of HFD-LOH mice with ML-SA1 treatment and TRT(c, nND = 200 cells, nVehicle = 326, nML-SA1=236, nTestosterone = 232; d, nND = 211 cells, nVehicle = 215, nML-SA1=216, nTestosterone = 199). e, DEG of SCs in ND and HFD treated with Vehicle or ML-SA1. f, GO analysis of ML-SA1 treatment effect on DEG of SCs between HFD vs ND. g, DEG of LCs in ND and HFD treated with Vehicle or ML-SA1. h, GO analysis of ML-SA1 treatment effect on DEG of LCs between HFD vs ND. At least five individual mice for each group. The boxes represent the median and interquartile range and the bars represent roughly 95% confidence interval for comparing medians (c). Data are presented as mean ± s.e.m (a, b). Comparison by two-tailed unpaired t-test.

Source data

Supplementary information

Supplementary Information

Schematic of improving lysosomal function of PALD SCs. The left panel shows that lysosomal dysfunction in PALD SCs leads to the accumulation of autolysosomes and phagolysosomes, abolishing its function as a metabolic coordinator in TME. The right panel shows that improving lysosomal function through the TRPML1 agonist effectively restores the degradation ability of SCs and the nutrient supply to surrounding cells.

Reporting Summary

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Deng, Z., Zhao, L., Li, S. et al. Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism. Nat Aging (2024). https://doi.org/10.1038/s43587-024-00614-2

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