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

PDF(58394 KB)
PDF(58394 KB)
Protein Cell ›› 2023, Vol. 14 ›› Issue (12) : 888-907. DOI: 10.1093/procel/pwac057
RESEARCH ARTICLE
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

Author information +
History +

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

Cite this article

Download citation ▾
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. A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis. Protein Cell, 2023, 14(12): 888‒907 https://doi.org/10.1093/procel/pwac057

References

[1]
Aging Atlas C. Aging Atlas: a multi-omics database for aging biology. Nucleic Acids Res 2021;49:D825–D830.
CrossRef Google scholar
[2]
Aibar S, González-Blas CB, Moerman T et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods 2017;14:1083–1086.
CrossRef Google scholar
[3]
Alfano M, Tascini AS, Pederzoli F et al. Aging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia. Nat Commun 2021;12:5205.
CrossRef Google scholar
[4]
Angelidis I, Simon LM, Fernandez IE et al. An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics. Nat Commun 2019;10:963.
CrossRef Google scholar
[5]
Bai L, Shi G, Zhang X et al. Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function. Exp Cell Res 2013;319:2739–2746.
CrossRef Google scholar
[6]
Bai S, Fu K, Yin H et al. Sox30 initiates transcription of haploid genes during late meiosis and spermiogenesis in mouse testes. Development (Cambridge, England) 2018;145:dev164855.
CrossRef Google scholar
[7]
Bao J, Rousseaux S, Shen J et al. The arginine methyltransferase CARM1 represses p300•ACT•CREMτ activity and is required for spermiogenesis. Nucleic Acids Res 2018;46:4327–4343.
CrossRef Google scholar
[8]
Basaria S. Reproductive aging in men. Endocrinol Metab Clin N Am 2013;42:255–270.
CrossRef Google scholar
[9]
Basu D, Hu Y, Huggins LA et al. Novel reversible model of atherosclerosis and regression using oligonucleotide regulation of the LDL receptor. Circ Res 2018;122:560–567.
CrossRef Google scholar
[10]
Butler A, Hoffman P, Smibert P et al. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 2018;36:411–420.
CrossRef Google scholar
[11]
Cai Y, Song W, Li J et al. The landscape of aging. Sci China Life Sci 2022;65:2354–2454.
CrossRef Google scholar
[12]
Cansby E, Magnusson E, Nuñez-Durán E et al. STK25 regulates cardiovascular disease progression in a mouse model of hypercholesterolemia. Arterioscler Thromb Vasc Biol 2018;38:1723–1737.
CrossRef Google scholar
[13]
Cao C, Ma Q, Mo S et al. Single-cell RNA sequencing defines the regulation of spermatogenesis by Sertoli-cell androgen signaling. Front Cell Dev Biol 2021;9:763267.
CrossRef Google scholar
[14]
Chang H, Gao F, Guillou F et al. Wt1 negatively regulates beta-catenin signaling during testis development. Development (Cambridge, England) 2008;135:1875–1885.
CrossRef Google scholar
[15]
Chen SR, Chen M, Wang XN et al. The Wilms tumor gene, Wt1, maintains testicular cord integrity by regulating the expression of Col4a1 and Col4a2. Biol Reprod 2013;88:56.
CrossRef Google scholar
[16]
Chhabra SN, Booth BW. Asymmetric cell division of mammary stem cells. Cell Div 2021;16:5.
CrossRef Google scholar
[17]
Debacq-Chainiaux F, Erusalimsky JD, Campisi J 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.
CrossRef Google scholar
[18]
Dym M. The fine structure of the monkey (Macaca) Sertoli cell and its role in maintaining the blood-testis barrier. Anatom Rec 1973;175:639–656.
CrossRef Google scholar
[19]
Dym M, Fawcett DW. The blood-testis barrier in the rat and the physiological compartmentation of the seminiferous epithelium. Biol Reprod 1970;3:308–326.
CrossRef Google scholar
[20]
Efremova M, Vento-Tormo M, Teichmann SA et al. CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes. Nat Protoc 2020;15:1484–1506.
CrossRef Google scholar
[21]
Fang X, Huang LL, Xu J 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.
CrossRef Google scholar
[22]
Fang X, Jiang M, Zhou M et al. Elucidating the developmental dynamics of mouse stromal cells at single-cell level. Life Med 2022;1:45–48.
CrossRef Google scholar
[23]
Fayomi AP, Orwig KE. Spermatogonial stem cells and spermatogenesis in mice, monkeys and men. Stem Cell Res 2018;29:207–214.
CrossRef Google scholar
[24]
Finkelstein JS, Lee H, Burnett-Bowie SA et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013;369:1011–1022.
CrossRef Google scholar
[25]
Fleming SJ, Marioni JC, Babadi M. CellBender remove-background: a deep generative model for unsupervised removal of background noise from scRNA-seq datasets. bioRxiv 2019;791699.
[26]
Florian MC, Geiger H. Concise review: polarity in stem cells, disease, and aging. Stem Cells 2010;28:1623–1629.
CrossRef Google scholar
[27]
Ganapathy AS, Saha K, Suchanec E 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.
CrossRef Google scholar
[28]
Georgakopoulou EA, Tsimaratou K, Evangelou K 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.
CrossRef Google scholar
[29]
Goodell MA, Rando TA. Stem cells and healthy aging. Science 2015;350:1199–1204.
CrossRef Google scholar
[30]
Gregoire EP, Stevant I, Chassot AA et al. NRG1 signalling regulates the establishment of Sertoli cell stock in the mouse testis. Mol Cell Endocrinol 2018;478:17–31.
CrossRef Google scholar
[31]
Griswold MD. Interactions between germ cells and Sertoli cells in the testis. Biol Reprod 1995;52:211–216.
CrossRef Google scholar
[32]
Griswold MD. The central role of Sertoli cells in spermatogenesis. Semin Cell Dev Biol 1998;9:411–416.
CrossRef Google scholar
[33]
Gunes S, Hekim GN, Arslan MA et al. Effects of aging on the male reproductive system. J Assist Reprod Genet 2016;33:441–454.
CrossRef Google scholar
[34]
Hastie ND. Wilms’ tumour 1 (WT1) in development, homeostasis and disease. Development (Cambridge, England) 2017;144:2862–2872.
CrossRef Google scholar
[35]
Heinrich A, DeFalco T. Essential roles of interstitial cells in testicular development and function. Andrology 2020;8:903–914.
CrossRef Google scholar
[36]
Huang G, Liu L, Wang H et al. Tet1 deficiency leads to premature reproductive aging by reducing spermatogonia stem cells and germ cell differentiation. iScience 2020;23:100908.
CrossRef Google scholar
[37]
Inaba M, Yamashita YM. Asymmetric stem cell division: precision for robustness. Cell Stem Cell 2012;11:461–469.
CrossRef Google scholar
[38]
Inagaki M, Irie K, Ishizaki H et al. Role of cell adhesion molecule nectin-3 in spermatid development. Genes Cells Devoted Mol Cell Mech 2006;11:1125–1132.
CrossRef Google scholar
[39]
Ito C, Akutsu H, Yao R et al. Odf2 haploinsufficiency causes a new type of decapitated and decaudated spermatozoa, Odf2-DDS, in mice. Sci Rep 2019;9:14249.
CrossRef Google scholar
[40]
Johnson L, Nguyen HB, Petty CS 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.
CrossRef Google scholar
[41]
Kallio M, Chang Y, Manuel M et al. Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice. EMBO J 2002;21:2591–2601.
CrossRef Google scholar
[42]
Kanehisa M, Furumichi M, Sato Y et al. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res 2021;49:D545–D551.
CrossRef Google scholar
[43]
Kaufman BA, Van Houten B. POLB: A new role of DNA polymerase beta in mitochondrial base excision repair. DNA Repair (Amst) 2017;60:A1–A5.
CrossRef Google scholar
[44]
Kaufman JM, Lapauw B, Mahmoud A et al. Aging and the male reproductive system. Endocr Rev 2019;40:906–972.
CrossRef Google scholar
[45]
Kaur G, Thompson LA, Dufour JM. Sertoli cells—immunological sentinels of spermatogenesis. Semin Cell Dev Biol 2014;30:36–44.
CrossRef Google scholar
[46]
Khawar MB, Liu C, Gao F et al. Sirt1 regulates testosterone biosynthesis in Leydig cells via modulating autophagy. Protein Cell 2021;12:67–75.
CrossRef Google scholar
[47]
Komeya M, Ogawa T. Spermatogonial stem cells: Progress and prospects. Asian J Androl 2015;17:771–775.
CrossRef Google scholar
[48]
Kovalenko OV, Wiese C, Schild D. 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.
CrossRef Google scholar
[49]
Krishnaswami SR, Grindberg RV, Novotny M et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat Protoc 2016;11:499–524.
CrossRef Google scholar
[50]
Kubota H, Brinster RLJBR. Spermatogonial stem cells†. Biol Reprod 2018;99:52–74.
CrossRef Google scholar
[51]
Lahoud MH, Ristevski S, Venter DJ 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.
CrossRef Google scholar
[52]
Lee JJ, Park IH, Kwak MS et al. HMGB1 orchestrates STING-mediated senescence via TRIM30α modulation in cancer cells. Cell Death Discov 2021;7:28.
CrossRef Google scholar
[53]
Lee JJ, Park IH, Rhee WJ et al. HMGB1 modulates the balance between senescence and apoptosis in response to genotoxic stress. FASEB J 2019;33:10942–10953.
CrossRef Google scholar
[54]
Li J, Zheng Y, Yan P et al. A single-cell transcriptomic atlas of primate pancreatic islet aging. Natl Sci Rev 2021;8:nwaa127.
CrossRef Google scholar
[55]
Liberzon A, Birger C, Thorvaldsdóttir H et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 2015;1:417–425.
CrossRef Google scholar
[56]
Lim S, Kierzek M, O’Connor AE et al. CRISP2 is a regulator of multiple aspects of sperm function and male fertility. Endocrinology 2019;160:915–924.
CrossRef Google scholar
[57]
Liu J, Weaver J, Jin X 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.
CrossRef Google scholar
[58]
Luo J, Gupta V, Kern B et al. Role of FYN kinase in spermatogenesis: defects characteristic of Fyn-null sperm in mice. Biol Reprod 2012;86:1–8.
CrossRef Google scholar
[59]
Ma S, Sun S, Geng L et al. Caloric restriction reprograms the single-cell transcriptional landscape of Rattus norvegicus aging. Cell 2020;180:984–1001.e22.
CrossRef Google scholar
[60]
Ma S, Sun S, Li J et al. Single-cell transcriptomic atlas of primate cardiopulmonary aging. Cell Res 2021;31:415–432.
CrossRef Google scholar
[61]
Ma S, Wang S, Ye Y et al. Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues. Cell Stem Cell 2022;29:990–1005.e10.
CrossRef Google scholar
[62]
Maekawa M, Ito C, Toyama Y 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.
CrossRef Google scholar
[63]
Maekawa M, Toyama Y, Yasuda M et al. Fyn tyrosine kinase in Sertoli cells is involved in mouse spermatogenesis. Biol Reprod 2002;66:211–221.
CrossRef Google scholar
[64]
Matzkin ME, Calandra RS, Rossi SP 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.
CrossRef Google scholar
[65]
McGinnis CS, Murrow LM, Gartner ZJ. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst 2019;8:329–337.e4.
CrossRef Google scholar
[66]
Metcalf CE, Wassarman DA. Nucleolar colocalization of TAF1 and testis-specific TAFs during Drosophila spermatogenesis. Dev Dyn 2007;236:2836–2843.
CrossRef Google scholar
[67]
Miquel J, Lundgren PR, Johnson JE Jr. Spectrophotofluorometric and electron microscopic study of lipofuscin accumulation in the testis of aging mice. J Gerontol 1978;33:3–19.
CrossRef Google scholar
[68]
Mo H, He J, Yuan Z 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.
CrossRef Google scholar
[69]
Moerman T, Aibar Santos S, Bravo González-Blas C et al. GRNBoost2 and Arboreto: efficient and scalable inference of gene regulatory networks. Bioinformatics (Oxford, England) 2019;35:2159–2161.
CrossRef Google scholar
[70]
Nie X, Munyoki SK, Sukhwani M, Schmid N, Missel A, Emery BR, DonorConnect, Stukenborg JB, Mayerhofer A, Orwig KE et al. Single-cell analysis of human testis aging and correlation with elevated body mass index. Dev Cell 2022;57:1160–1176e5.
CrossRef Google scholar
[71]
Nishino J, Kim I, Chada K 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.
CrossRef Google scholar
[72]
O’Donnell L, Smith LB, Rebourcet D. Sertoli cells as key drivers of testis function. Semin Cell Dev Biol 2022;121:2–9.
CrossRef Google scholar
[73]
Oatley JM, Brinster RL. The germline stem cell niche unit in mammalian testes. Physiol Rev 2012;92:577–595.
CrossRef Google scholar
[74]
Oatley JM, Brinster RLJM. Spermatogonial stem cells. Methods Enzymol 2006;419:259–282.
CrossRef Google scholar
[75]
Oral O, Uchida I, Eto K et al. Promotion of spermatogonial proliferation by neuregulin 1 in newt (Cynops pyrrhogaster) testis. Mech Dev 2008;125:906–917.
CrossRef Google scholar
[76]
Paniagua R, Nistal M, Sáez FJ et al. Ultrastructure of the aging human testis. J Electron Microsc Tech 1991;19:241–260.
CrossRef Google scholar
[77]
Perheentupa A, Huhtaniemi I. Aging of the human ovary and testis. Mol Cell Endocrinol 2009;299:2–13.
CrossRef Google scholar
[78]
Piñero J, Ramírez-Anguita JM, Saüch-Pitarch J et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res 2020;48:D845–D855.
CrossRef Google scholar
[79]
Sampson N, Untergasser G, Plas E et al. The ageing male reproductive tract. J Pathol 2007;211:206–218.
CrossRef Google scholar
[80]
Schwayer C, Shamipour S, Pranjic-Ferscha K, Schauer A, Balda M, Tada M, Matter K, Heisenberg CP. Mechanosensation of tight junctions depends on ZO-1 phase separation and flow. Cell 2019;179:937–952.e18.e18.
CrossRef Google scholar
[81]
Shah W, Khan R, Shah B et al. The molecular mechanism of sex hormones on Sertoli cell development and proliferation. Front Endocrinol (Lausanne) 2021;12:648141.
CrossRef Google scholar
[82]
Shannon P, Markiel A, Ozier O et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13:2498–2504.
CrossRef Google scholar
[83]
Shi L, Zhou T, Huang Q et al. Intraflagellar transport protein 74 is essential for spermatogenesis and male fertility in mice†. Biol Reprod 2019;101:188–199.
CrossRef Google scholar
[84]
Siu MK, Cheng CY. Extracellular matrix and its role in spermatogenesis. Adv Exp Med Biol 2008;636:74–91.
CrossRef Google scholar
[85]
Stewart AG, Thomas B, Koff J. TGF-β: master regulator of inflammation and fibrosis. Respirology (Carlton, Vic) 2018;23:1096–1097.
CrossRef Google scholar
[86]
Syed V, Hecht NB. Disruption of germ cell–Sertoli cell interactions leads to spermatogenic defects. Mol Cell Endocrinol 2002;186:155–157.
CrossRef Google scholar
[87]
Trapnell C, Cacchiarelli D, Grimsby J et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol 2014;32:381–386.
CrossRef Google scholar
[88]
Umehara T, Kawashima I, Kawai T et al. Neuregulin 1 regulates proliferation of leydig cells to support spermatogenesis and sexual behavior in adult mice. Endocrinology 2016;157:4899–4913.
CrossRef Google scholar
[89]
Urban N, Blomfield IM, Guillemot F. Quiescence of adult mammalian neural stem cells: a highly regulated rest. Neuron 2019;104:834–848.
CrossRef Google scholar
[90]
Wang G, Zhang J, Moskophidis D 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.
CrossRef Google scholar
[91]
Wang RS, Yeh S, Tzeng CR et al. Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice. Endocr Rev 2009;30:119–132.
CrossRef Google scholar
[92]
Wang S, Cheng F, Ji Q et al. Hyperthermia differentially affects specific human stem cells and their differentiated derivatives. Protein Cell 2022a;13:615–622.
CrossRef Google scholar
[93]
Wang S, Hu B, Ding Z et al. ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells. Cell Discov 2018;4:2.
CrossRef Google scholar
[94]
Wang S, Yao X, Ma S et al. A single-cell transcriptomic landscape of the lungs of patients with COVID-19. Nat Cell Biol 2021a;23:1314–1328.
CrossRef Google scholar
[95]
Wang S, Zheng Y, Li Q et al. Deciphering primate retinal aging at single-cell resolution. Protein Cell 2021b;12:889–898.
CrossRef Google scholar
[96]
Wang X, Adegoke EO, Ma M 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.
CrossRef Google scholar
[97]
Wang X, Cairns BR, Guo J. When spermatogenesis meets human aging and elevated body mass. Life Med 2022b;lnac022.
CrossRef Google scholar
[98]
Wickham H. ggplot2: elegant graphics for data analysis. Cham: Springer, 2016.
CrossRef Google scholar
[99]
Wiener-Megnazi Z, Auslender R, Dirnfeld, M. Advanced paternal age and reproductive outcome. Asian J Androl 2012;14:69–76.
CrossRef Google scholar
[100]
Wong CH, Cheng CY. The blood-testis barrier: its biology, regulation, and physiological role in spermatogenesis. Curr Top Dev Biol 2005;71:263–296.
CrossRef Google scholar
[101]
Yan RG, Yang QL, Yang QE. E4 Transcription Factor 1 (E4F1) regulates sertoli cell proliferation and fertility in mice. Anim Open Access J MDPI 2020;10:1691.
CrossRef Google scholar
[102]
Zhang H, Li J, Ren J et al. Single-nucleus transcriptomic landscape of primate hippocampal aging. Protein Cell 2021;12:695–716.
CrossRef Google scholar
[103]
Zhang L, Chen M, Wen Q et al. Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation. Proc Natl Acad Sci USA 2015;112:4003–4008.
CrossRef Google scholar
[104]
Zhang S, An Q, Wang T 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.
CrossRef Google scholar
[105]
Zhang T, Oatley J, Bardwell VJ et al. DMRT1 is required for mouse spermatogonial stem cell maintenance and replenishment. PLoS Genet 2016a;12:e1006293.
CrossRef Google scholar
[106]
Zhang W, Zhang S, Yan P et al. A single-cell transcriptomic landscape of primate arterial aging. Nat Commun 2020;11:2202.
CrossRef Google scholar
[107]
Zhang Y, Zhang D, Li Q et al. Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering. Nat Genet 2016b;48:1003–1013.
CrossRef Google scholar
[108]
Zhang Y, Zheng Y, Wang S et al. Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging. Protein Cell 2023;14:279–293.
CrossRef Google scholar
[109]
Zhao H, Ma N, Chen Q et al. Decline in testicular function in ageing rats: changes in the unfolded protein response and mitochondrial apoptotic pathway. Exp Gerontol 2019;127:110721.
CrossRef Google scholar
[110]
Zhong S, Ding W, Sun L et al. Decoding the development of the human hippocampus. Nature 2020;577:531–536.
CrossRef Google scholar
[111]
Zhou Y, Zhou B, Pache L et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019;10:1523.
CrossRef Google scholar
[112]
Zirkin BR, Tenover JL. Aging and declining testosterone: past, present, and hopes for the future. J Androl 2012;33:1111–1118.
CrossRef Google scholar
[113]
Zou X, Dai X, Mentis A-FA et al. From monkey single-cell atlases into a broader biomedical perspective. Life Med 2022;lnac028.
CrossRef Google scholar
[114]
Zou Z, Long X, Zhao Q et al. A single-cell transcriptomic atlas of human skin aging. Dev Cell 2021;56:383–397.e8.
CrossRef Google scholar

RIGHTS & PERMISSIONS

2022 The Author(s) 2022. Published by Oxford University Press on behalf of Higher Education Press.
AI Summary AI Mindmap
PDF(58394 KB)

Accesses

Citations

Detail

Sections
Recommended

/