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

doi:10.1093/procel/pwac057

Protein Cell

2023, Vol. 14

Issue (12) : 888-907 https://doi.org/10.1093/procel/pwac057

RESEARCH ARTICLE

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^1,³, Yuesheng Zuo^5,^7,⁹, Chen Zhang¹⁰, Guoqiang Sun^2,⁵, Ying Jing^2,⁵, Jinghui Lei^1,³, Shuai Ma^4,^6,^8,¹⁶, Shuhui Sun^4,^6,⁸, Huifen Lu^1,³, Yusheng Cai^4,^6,⁸, Weiqi Zhang^5,^7,^8,^9,^11,^12,¹⁶, Fei Gao^2,^5,^6,⁸, Andy Peng Xiang^13,¹⁴, Juan Carlos Izpisua Belmonte¹⁵, Guang-Hui Liu^1,^3,^4,^5,^6,^8,¹⁶(

), Jing Qu^2,^5,^6,^8,¹⁶(

), Si Wang^1,^3,^10,¹⁶(

)

¹. Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
². State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
³. Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
⁴. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
⁵. University of Chinese Academy of Sciences, Beijing 100049, China
⁶. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
⁷. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
⁸. Institute for Stem cell and Regeneration, CAS, Beijing 100101, China
⁹. China National Center for Bioinformation, Beijing 100101, China
¹⁰. The Fifth People’s Hospital of Chongqing, Chongqing 400062, China
¹¹. Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China
¹². Sino-Danish Center for Education and Research, Beijing 101408, China
¹³. 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
¹⁴. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510000, China
¹⁵. Altos Labs, Inc., San Diego, CA 92121, USA and
¹⁶. Aging Biomarker Consortium, China

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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.

Keywords single-nucleus RNA sequencing primate testis aging WT1

Corresponding Author(s): Guang-Hui Liu,Jing Qu,Si Wang

Issue Date: 25 December 2023

Cite this article:

Daoyuan Huang,Yuesheng Zuo,Chen Zhang, et al. A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis[J]. Protein Cell, 2023, 14(12): 888-907.

URL:

https://academic.hep.com.cn/pac/EN/10.1093/procel/pwac057
https://academic.hep.com.cn/pac/EN/Y2023/V14/I12/888

1	C. Aging Atlas Aging Atlas: a multi-omics database for aging biology. Nucleic Acids Res 2021;49:D825–D830. https://doi.org/10.1093/nar/gkaa894
2	S Aibar, CB González-Blas, T Moerman et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods 2017;14:1083–1086. https://doi.org/10.1038/nmeth.4463
3	M Alfano, AS Tascini, F Pederzoli et al. Aging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia. Nat Commun 2021;12:5205. https://doi.org/10.1038/s41467-021-25544-0
4	I Angelidis, LM Simon, IE Fernandez et al. An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics. Nat Commun 2019;10:963. https://doi.org/10.1038/s41467-019-08831-9
5	L Bai, G Shi, X Zhang et al. Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function. Exp Cell Res 2013;319:2739–2746. https://doi.org/10.1016/j.yexcr.2013.06.014
6	S Bai, K Fu, H Yin et al. Sox30 initiates transcription of haploid genes during late meiosis and spermiogenesis in mouse testes. Development (Cambridge, England) 2018;145:dev164855. https://doi.org/10.1242/dev.164855
7	J Bao, S Rousseaux, J Shen et al. The arginine methyltransferase CARM1 represses p300•ACT•CREMτ activity and is required for spermiogenesis. Nucleic Acids Res 2018;46:4327–4343. https://doi.org/10.1093/nar/gky240
8	S. Basaria Reproductive aging in men. Endocrinol Metab Clin N Am 2013;42:255–270. https://doi.org/10.1016/j.ecl.2013.02.012
9	D Basu, Y Hu, LA Huggins et al. Novel reversible model of atherosclerosis and regression using oligonucleotide regulation of the LDL receptor. Circ Res 2018;122:560–567. https://doi.org/10.1161/CIRCRESAHA.117.311361
10	A Butler, P Hoffman, P Smibert et al. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 2018;36:411–420. https://doi.org/10.1038/nbt.4096
11	Y Cai, W Song, J Li et al. The landscape of aging. Sci China Life Sci 2022;65:2354–2454. https://doi.org/10.1007/s11427-022-2161-3
12	E Cansby, E Magnusson, E Nuñez-Durán et al. STK25 regulates cardiovascular disease progression in a mouse model of hypercholesterolemia. Arterioscler Thromb Vasc Biol 2018;38:1723–1737. https://doi.org/10.1161/ATVBAHA.118.311241
13	C Cao, Q Ma, S Mo et al. Single-cell RNA sequencing defines the regulation of spermatogenesis by Sertoli-cell androgen signaling. Front Cell Dev Biol 2021;9:763267. https://doi.org/10.3389/fcell.2021.763267
14	H Chang, F Gao, F Guillou et al. Wt1 negatively regulates beta-catenin signaling during testis development. Development (Cambridge, England) 2008;135:1875–1885. https://doi.org/10.1242/dev.018572
15	SR Chen, M Chen, XN Wang et al. The Wilms tumor gene, Wt1, maintains testicular cord integrity by regulating the expression of Col4a1 and Col4a2. Biol Reprod 2013;88:56. https://doi.org/10.1095/biolreprod.112.105379
16	SN Chhabra, BW. Booth Asymmetric cell division of mammary stem cells. Cell Div 2021;16:5. https://doi.org/10.1186/s13008-021-00073-w
17	F Debacq-Chainiaux, JD Erusalimsky, J Campisi et al. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 2009;4:1798–1806. https://doi.org/10.1038/nprot.2009.191
18	M. Dym The fine structure of the monkey (Macaca) Sertoli cell and its role in maintaining the blood-testis barrier. Anatom Rec 1973;175:639–656. https://doi.org/10.1002/ar.1091750402
19	M Dym, DW. Fawcett The blood-testis barrier in the rat and the physiological compartmentation of the seminiferous epithelium. Biol Reprod 1970;3:308–326. https://doi.org/10.1093/biolreprod/3.3.308
20	M Efremova, M Vento-Tormo, SA Teichmann et al. CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes. Nat Protoc 2020;15:1484–1506. https://doi.org/10.1038/s41596-020-0292-x
21	X Fang, LL Huang, J Xu et al. Proteomics and single-cell RNA analysis of Akap4-knockout mice model confirm indispensable role of Akap4 in spermatogenesis. Dev Biol 2019;454:118–127. https://doi.org/10.1016/j.ydbio.2019.06.017
22	X Fang, M Jiang, M Zhou et al. Elucidating the developmental dynamics of mouse stromal cells at single-cell level. Life Med 2022;1:45–48. https://doi.org/10.1093/lifemedi/lnac037
23	AP Fayomi, KE. Orwig Spermatogonial stem cells and spermatogenesis in mice, monkeys and men. Stem Cell Res 2018;29:207–214. https://doi.org/10.1016/j.scr.2018.04.009
24	JS Finkelstein, H Lee, SA Burnett-Bowie et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013;369:1011–1022. https://doi.org/10.1056/NEJMoa1206168
25	SJ Fleming, JC Marioni, M. Babadi CellBender remove-background: a deep generative model for unsupervised removal of background noise from scRNA-seq datasets. bioRxiv 2019;791699.
26	MC Florian, H. Geiger Concise review: polarity in stem cells, disease, and aging. Stem Cells 2010;28:1623–1629. https://doi.org/10.1002/stem.481
27	AS Ganapathy, K Saha, E Suchanec et al. AP2M1 mediates autophagy-induced CLDN2 (claudin 2) degradation through endocytosis and interaction with LC3 and reduces intestinal epithelial tight junction permeability. Autophagy 2022;18:2086–2103. https://doi.org/10.1080/15548627.2021.2016233
28	EA Georgakopoulou, K Tsimaratou, K Evangelou et al. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging 2013;5:37–50. https://doi.org/10.18632/aging.100527
29	MA Goodell, TA. Rando Stem cells and healthy aging. Science 2015;350:1199–1204. https://doi.org/10.1126/science.aab3388
30	EP Gregoire, I Stevant, AA Chassot et al. NRG1 signalling regulates the establishment of Sertoli cell stock in the mouse testis. Mol Cell Endocrinol 2018;478:17–31. https://doi.org/10.1016/j.mce.2018.07.004
31	MD. Griswold Interactions between germ cells and Sertoli cells in the testis. Biol Reprod 1995;52:211–216. https://doi.org/10.1095/biolreprod52.2.211
32	MD. Griswold The central role of Sertoli cells in spermatogenesis. Semin Cell Dev Biol 1998;9:411–416. https://doi.org/10.1006/scdb.1998.0203
33	S Gunes, GN Hekim, MA Arslan et al. Effects of aging on the male reproductive system. J Assist Reprod Genet 2016;33:441–454. https://doi.org/10.1007/s10815-016-0663-y
34	ND. Hastie Wilms’ tumour 1 (WT1) in development, homeostasis and disease. Development (Cambridge, England) 2017;144:2862–2872. https://doi.org/10.1242/dev.153163
35	A Heinrich, T. DeFalco Essential roles of interstitial cells in testicular development and function. Andrology 2020;8:903–914. https://doi.org/10.1111/andr.12703
36	G Huang, L Liu, H Wang et al. Tet1 deficiency leads to premature reproductive aging by reducing spermatogonia stem cells and germ cell differentiation. iScience 2020;23:100908. https://doi.org/10.1016/j.isci.2020.100908
37	M Inaba, YM. Yamashita Asymmetric stem cell division: precision for robustness. Cell Stem Cell 2012;11:461–469. https://doi.org/10.1016/j.stem.2012.09.003
38	M Inagaki, K Irie, H Ishizaki et al. Role of cell adhesion molecule nectin-3 in spermatid development. Genes Cells Devoted Mol Cell Mech 2006;11:1125–1132. https://doi.org/10.1111/j.1365-2443.2006.01006.x
39	C Ito, H Akutsu, R Yao et al. Odf2 haploinsufficiency causes a new type of decapitated and decaudated spermatozoa, Odf2-DDS, in mice. Sci Rep 2019;9:14249. https://doi.org/10.1038/s41598-019-50516-2
40	L Johnson, HB Nguyen, CS Petty et al. Quantification of human spermatogenesis: germ cell degeneration during spermatocytogenesis and meiosis in testes from younger and older adult men. Biol Reprod 1987;37:739–747. https://doi.org/10.1095/biolreprod37.3.739
41	M Kallio, Y Chang, M Manuel et al. Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice. EMBO J 2002;21:2591–2601. https://doi.org/10.1093/emboj/21.11.2591
42	M Kanehisa, M Furumichi, Y Sato et al. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res 2021;49:D545–D551. https://doi.org/10.1093/nar/gkaa970
43	BA Kaufman, B. Van Houten POLB: A new role of DNA polymerase beta in mitochondrial base excision repair. DNA Repair (Amst) 2017;60:A1–A5. https://doi.org/10.1016/j.dnarep.2017.11.002
44	JM Kaufman, B Lapauw, A Mahmoud et al. Aging and the male reproductive system. Endocr Rev 2019;40:906–972. https://doi.org/10.1210/er.2018-00178
45	G Kaur, LA Thompson, JM. Dufour Sertoli cells—immunological sentinels of spermatogenesis. Semin Cell Dev Biol 2014;30:36–44. https://doi.org/10.1016/j.semcdb.2014.02.011
46	MB Khawar, C Liu, F Gao et al. Sirt1 regulates testosterone biosynthesis in Leydig cells via modulating autophagy. Protein Cell 2021;12:67–75. https://doi.org/10.1007/s13238-020-00771-1
47	M Komeya, T. Ogawa Spermatogonial stem cells: Progress and prospects. Asian J Androl 2015;17:771–775. https://doi.org/10.4103/1008-682X.154995
48	OV Kovalenko, C Wiese, D. Schild RAD51AP2, a novel vertebrate- and meiotic-specific protein, shares a conserved RAD51-interacting C-terminal domain with RAD51AP1/PIR51. Nucleic Acids Res 2006;34:5081–5092. https://doi.org/10.1093/nar/gkl665
49	SR Krishnaswami, RV Grindberg, M Novotny et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat Protoc 2016;11:499–524. https://doi.org/10.1038/nprot.2016.015
50	H Kubota, RLJBR. Brinster Spermatogonial stem cells†. Biol Reprod 2018;99:52–74. https://doi.org/10.1093/biolre/ioy077
51	MH Lahoud, S Ristevski, DJ Venter et al. Gene targeting of Desrt, a novel ARID class DNA-binding protein, causes growth retardation and abnormal development of reproductive organs. Genome Res 2001;11:1327–1334. https://doi.org/10.1101/gr.168801
52	JJ Lee, IH Park, MS Kwak et al. HMGB1 orchestrates STING-mediated senescence via TRIM30α modulation in cancer cells. Cell Death Discov 2021;7:28. https://doi.org/10.1038/s41420-021-00409-z
53	JJ Lee, IH Park, WJ Rhee et al. HMGB1 modulates the balance between senescence and apoptosis in response to genotoxic stress. FASEB J 2019;33:10942–10953. https://doi.org/10.1096/fj.201900288R
54	J Li, Y Zheng, P Yan et al. A single-cell transcriptomic atlas of primate pancreatic islet aging. Natl Sci Rev 2021;8:nwaa127. https://doi.org/10.1093/nsr/nwaa127
55	A Liberzon, C Birger, H Thorvaldsdóttir et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 2015;1:417–425. https://doi.org/10.1016/j.cels.2015.12.004
56	S Lim, M Kierzek, AE O’Connor et al. CRISP2 is a regulator of multiple aspects of sperm function and male fertility. Endocrinology 2019;160:915–924. https://doi.org/10.1210/en.2018-01076
57	J Liu, J Weaver, X Jin et al. Nitric oxide interacts with Caveolin-1 to facilitate autophagy-lysosome-mediated Claudin-5 degradation in oxygen-glucose deprivation-treated endothelial cells. Mol Neurobiol 2016;53:5935–5947. https://doi.org/10.1007/s12035-015-9504-8
58	J Luo, V Gupta, B Kern et al. Role of FYN kinase in spermatogenesis: defects characteristic of Fyn-null sperm in mice. Biol Reprod 2012;86:1–8. https://doi.org/10.1095/biolreprod.111.093864
59	S Ma, S Sun, L Geng et al. Caloric restriction reprograms the single-cell transcriptional landscape of Rattus norvegicus aging. Cell 2020;180:984–1001.e22. https://doi.org/10.1016/j.cell.2020.02.008
60	S Ma, S Sun, J Li et al. Single-cell transcriptomic atlas of primate cardiopulmonary aging. Cell Res 2021;31:415–432. https://doi.org/10.1038/s41422-020-00412-6
61	S Ma, S Wang, Y Ye et al. Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues. Cell Stem Cell 2022;29:990–1005.e10. https://doi.org/10.1016/j.stem.2022.04.017
62	M Maekawa, C Ito, Y Toyama et al. Localisation of RA175 (Cadm1), a cell adhesion molecule of the immunoglobulin superfamily, in the mouse testis, and analysis of male infertility in the RA175-deficient mouse. Andrologia 2011;43:180–188. https://doi.org/10.1111/j.1439-0272.2010.01049.x
63	M Maekawa, Y Toyama, M Yasuda et al. Fyn tyrosine kinase in Sertoli cells is involved in mouse spermatogenesis. Biol Reprod 2002;66:211–221. https://doi.org/10.1095/biolreprod66.1.211
64	ME Matzkin, RS Calandra, SP Rossi et al. Hallmarks of testicular aging: the challenge of anti-inflammatory and antioxidant therapies using natural and/or pharmacological compounds to improve the physiopathological status of the aged male gonad. Cells 2021;10:3114. https://doi.org/10.3390/cells10113114
65	CS McGinnis, LM Murrow, ZJ. Gartner DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst 2019;8:329–337.e4. https://doi.org/10.1016/j.cels.2019.03.003
66	CE Metcalf, DA. Wassarman Nucleolar colocalization of TAF1 and testis-specific TAFs during Drosophila spermatogenesis. Dev Dyn 2007;236:2836–2843. https://doi.org/10.1002/dvdy.21294
67	J Miquel, PR Lundgren, JE Jr. Johnson Spectrophotofluorometric and electron microscopic study of lipofuscin accumulation in the testis of aging mice. J Gerontol 1978;33:3–19. https://doi.org/10.1093/geronj/33.1.5
68	H Mo, J He, Z Yuan et al. WT1 is involved in the Akt-JNK pathway dependent autophagy through directly regulating Gas1 expression in human osteosarcoma cells. Biochem Biophys Res Commun 2016;478:74–80. https://doi.org/10.1016/j.bbrc.2016.07.090
69	T Moerman, S Aibar Santos, C Bravo González-Blas et al. GRNBoost2 and Arboreto: efficient and scalable inference of gene regulatory networks. Bioinformatics (Oxford, England) 2019;35:2159–2161. https://doi.org/10.1093/bioinformatics/bty916
70	X Nie, SK Munyoki, M Sukhwani, N Schmid, A Missel, BR Emery, DonorConnect, JB Stukenborg, A Mayerhofer, KE Orwig et al. Single-cell analysis of human testis aging and correlation with elevated body mass index. Dev Cell 2022;57:1160–1176e5. https://doi.org/10.1016/j.devcel.2022.04.004
71	J Nishino, I Kim, K Chada et al. Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell 2008;135:227–239. https://doi.org/10.1016/j.cell.2008.09.017
72	L O’Donnell, LB Smith, D. Rebourcet Sertoli cells as key drivers of testis function. Semin Cell Dev Biol 2022;121:2–9. https://doi.org/10.1016/j.semcdb.2021.06.016
73	JM Oatley, RL. Brinster The germline stem cell niche unit in mammalian testes. Physiol Rev 2012;92:577–595. https://doi.org/10.1152/physrev.00025.2011
74	JM Oatley, RLJM. Brinster Spermatogonial stem cells. Methods Enzymol 2006;419:259–282. https://doi.org/10.1016/S0076-6879(06)19011-4
75	O Oral, I Uchida, K Eto et al. Promotion of spermatogonial proliferation by neuregulin 1 in newt (Cynops pyrrhogaster) testis. Mech Dev 2008;125:906–917. https://doi.org/10.1016/j.mod.2008.06.004
76	R Paniagua, M Nistal, FJ Sáez et al. Ultrastructure of the aging human testis. J Electron Microsc Tech 1991;19:241–260. https://doi.org/10.1002/jemt.1060190209
77	A Perheentupa, I. Huhtaniemi Aging of the human ovary and testis. Mol Cell Endocrinol 2009;299:2–13. https://doi.org/10.1016/j.mce.2008.11.004
78	J Piñero, JM Ramírez-Anguita, J Saüch-Pitarch et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res 2020;48:D845–D855. https://doi.org/10.1093/nar/gkz1021
79	N Sampson, G Untergasser, E Plas et al. The ageing male reproductive tract. J Pathol 2007;211:206–218. https://doi.org/10.1002/path.2077
80	C Schwayer, S Shamipour, K Pranjic-Ferscha, A Schauer, M Balda, M Tada, K Matter, CP. Heisenberg Mechanosensation of tight junctions depends on ZO-1 phase separation and flow. Cell 2019;179:937–952.e18.e18. https://doi.org/10.1016/j.cell.2019.10.006
81	W Shah, R Khan, B Shah et al. The molecular mechanism of sex hormones on Sertoli cell development and proliferation. Front Endocrinol (Lausanne) 2021;12:648141. https://doi.org/10.3389/fendo.2021.648141
82	P Shannon, A Markiel, O Ozier et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13:2498–2504. https://doi.org/10.1101/gr.1239303
83	L Shi, T Zhou, Q Huang et al. Intraflagellar transport protein 74 is essential for spermatogenesis and male fertility in mice†. Biol Reprod 2019;101:188–199. https://doi.org/10.1093/biolre/ioz071
84	MK Siu, CY. Cheng Extracellular matrix and its role in spermatogenesis. Adv Exp Med Biol 2008;636:74–91. https://doi.org/10.1007/978-0-387-09597-4_5
85	AG Stewart, B Thomas, J. Koff TGF-β: master regulator of inflammation and fibrosis. Respirology (Carlton, Vic) 2018;23:1096–1097. https://doi.org/10.1111/resp.13415
86	V Syed, NB. Hecht Disruption of germ cell–Sertoli cell interactions leads to spermatogenic defects. Mol Cell Endocrinol 2002;186:155–157. https://doi.org/10.1016/S0303-7207(01)00656-6
87	C Trapnell, D Cacchiarelli, J Grimsby et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol 2014;32:381–386. https://doi.org/10.1038/nbt.2859
88	T Umehara, I Kawashima, T Kawai et al. Neuregulin 1 regulates proliferation of leydig cells to support spermatogenesis and sexual behavior in adult mice. Endocrinology 2016;157:4899–4913. https://doi.org/10.1210/en.2016-1478
89	N Urban, IM Blomfield, F. Guillemot Quiescence of adult mammalian neural stem cells: a highly regulated rest. Neuron 2019;104:834–848. https://doi.org/10.1016/j.neuron.2019.09.026
90	G Wang, J Zhang, D Moskophidis et al. Targeted disruption of the heat shock transcription factor (hsf)-2 gene results in increased embryonic lethality, neuronal defects, and reduced spermatogenesis. Genesis (New York, NY: 2000) 2003;36:48–61. https://doi.org/10.1002/gene.10200
91	RS Wang, S Yeh, CR Tzeng et al. Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice. Endocr Rev 2009;30:119–132. https://doi.org/10.1210/er.2008-0025
92	S Wang, F Cheng, Q Ji et al. Hyperthermia differentially affects specific human stem cells and their differentiated derivatives. Protein Cell 2022a;13:615–622. https://doi.org/10.1007/s13238-021-00887-y
93	S Wang, B Hu, Z Ding et al. ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells. Cell Discov 2018;4:2. https://doi.org/10.1038/s41421-017-0003-0
94	S Wang, X Yao, S Ma et al. A single-cell transcriptomic landscape of the lungs of patients with COVID-19. Nat Cell Biol 2021a;23:1314–1328. https://doi.org/10.1038/s41556-021-00796-6
95	S Wang, Y Zheng, Q Li et al. Deciphering primate retinal aging at single-cell resolution. Protein Cell 2021b;12:889–898. https://doi.org/10.1007/s13238-020-00791-x
96	X Wang, EO Adegoke, M Ma et al. Influence of Wilms’ tumor suppressor gene WT1 on bovine Sertoli cells polarity and tight junctions via non-canonical WNT signaling pathway. Theriogenology 2019;138:84–93. https://doi.org/10.1016/j.theriogenology.2019.07.007
97	X Wang, BR Cairns, J. Guo When spermatogenesis meets human aging and elevated body mass. Life Med 2022b;lnac022. https://doi.org/10.1093/lifemedi/lnac022
98	H. Wickham ggplot2: elegant graphics for data analysis. Cham: Springer, 2016. https://doi.org/10.1007/978-3-319-24277-4
99	Z Wiener-Megnazi, R Auslender, M. Dirnfeld, Advanced paternal age and reproductive outcome. Asian J Androl 2012;14:69–76. https://doi.org/10.1038/aja.2011.69
100	CH Wong, CY. Cheng The blood-testis barrier: its biology, regulation, and physiological role in spermatogenesis. Curr Top Dev Biol 2005;71:263–296. https://doi.org/10.1016/S0070-2153(05)71008-5
101	RG Yan, QL Yang, QE. Yang E4 Transcription Factor 1 (E4F1) regulates sertoli cell proliferation and fertility in mice. Anim Open Access J MDPI 2020;10:1691. https://doi.org/10.3390/ani10091691
102	H Zhang, J Li, J Ren et al. Single-nucleus transcriptomic landscape of primate hippocampal aging. Protein Cell 2021;12:695–716. https://doi.org/10.1007/s13238-021-00852-9
103	L Zhang, M Chen, Q Wen et al. Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation. Proc Natl Acad Sci USA 2015;112:4003–4008. https://doi.org/10.1073/pnas.1422371112
104	S Zhang, Q An, T Wang et al. Autophagy- and MMP-2/9-mediated reduction and redistribution of ZO-1 contribute to hyperglycemia-increased blood-brain barrier permeability during early reperfusion in stroke. Neuroscience 2018;377:126–137. https://doi.org/10.1016/j.neuroscience.2018.02.035
105	T Zhang, J Oatley, VJ Bardwell et al. DMRT1 is required for mouse spermatogonial stem cell maintenance and replenishment. PLoS Genet 2016a;12:e1006293. https://doi.org/10.1371/journal.pgen.1006293
106	W Zhang, S Zhang, P Yan et al. A single-cell transcriptomic landscape of primate arterial aging. Nat Commun 2020;11:2202. https://doi.org/10.1038/s41467-020-15997-0
107	Y Zhang, D Zhang, Q Li et al. Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering. Nat Genet 2016b;48:1003–1013. https://doi.org/10.1038/ng.3635
108	Y Zhang, Y Zheng, S Wang et al. Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging. Protein Cell 2023;14:279–293. https://doi.org/10.1093/procel/pwac038
109	H Zhao, N Ma, Q Chen et al. Decline in testicular function in ageing rats: changes in the unfolded protein response and mitochondrial apoptotic pathway. Exp Gerontol 2019;127:110721. https://doi.org/10.1016/j.exger.2019.110721
110	S Zhong, W Ding, L Sun et al. Decoding the development of the human hippocampus. Nature 2020;577:531–536. https://doi.org/10.1038/s41586-019-1917-5
111	Y Zhou, B Zhou, L Pache et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019;10:1523. https://doi.org/10.1038/s41467-019-09234-6
112	BR Zirkin, JL. Tenover Aging and declining testosterone: past, present, and hopes for the future. J Androl 2012;33:1111–1118. https://doi.org/10.2164/jandrol.112.017160
113	X Zou, X Dai, A-FA Mentis et al. From monkey single-cell atlases into a broader biomedical perspective. Life Med 2022;lnac028. https://doi.org/10.1093/lifemedi/lnac028
114	Z Zou, X Long, Q Zhao et al. A single-cell transcriptomic atlas of human skin aging. Dev Cell 2021;56:383–397.e8. https://doi.org/10.1016/j.devcel.2020.11.002

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