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Single-cell transcriptomics identifies senescence-associated secretory phenotype (SASP) features of testicular aging in human.

ABSTRACT: The male reproductive system experiences degradation with age, predominantly impacting the testes. Testicular aging can result in failure to produce physiological testosterone levels, normal sperm concentrations, or both. However, we cannot predict the onset of testicular aging in advance. Using single-cell RNA sequencing (scRNA-seq) from Gene Expression Omnibus (GEO) database, we conducted cell-cell communication network of human testis between older and young group, indicating Leydig cells' potential role in spermatogenesis microenvironment of aging testis. And we depicted the senescence-Associated Secretory Phenotype (SASP) features of aging testis by identifying differentially expressed senescence-associated secretory phenotype (SASP)-related genes between two group. Notably, IGFBP7 mainly expressed in Leydig cells of those differentially expressed SASP-related genes in aging testis. Furthermore, IGFBP7 protein located in the interstitial compartment of older mice confirmed by immunofluorescence and highly expressed in both human seminal plasma and mouse testis in the older group confirmed through Western blot. Together, our findings suggest that IGFBP7 may be a new biomarker of testicular aging.

SUBMITTER: He J

PROVIDER: S-EPMC10929807 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Single-cell transcriptomics identifies senescence-associated secretory phenotype (SASP) features of testicular aging in human.

He Junxian J Li Jindong J Li Yanqing Y Xu Zhenhan Z Ma Menghui M Chen Haicheng H Chen Peigen P Lv Linyan L Shang Xuejun X Liu Guihua G

Aging 20240212 4

The male reproductive system experiences degradation with age, predominantly impacting the testes. Testicular aging can result in failure to produce physiological testosterone levels, normal sperm concentrations, or both. However, we cannot predict the onset of testicular aging in advance. Using single-cell RNA sequencing (scRNA-seq) from Gene Expression Omnibus (GEO) database, we conducted cell-cell communication network of human testis between older and young group, indicating Leydig cells' po ...[more]

PMID: 38349859

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Project description:BackgroundDisturbed flow (d-flow)-induced senescence and activation of endothelial cells (ECs) have been suggested to have critical roles in promoting atherosclerosis. Telomeric repeat-binding factor 2 (TERF2)-interacting protein (TERF2IP), a member of the shelterin complex at the telomere, regulates the senescence-associated secretory phenotype (SASP), in which EC activation and senescence are engendered simultaneously by p90RSK-induced phosphorylation of TERF2IP S205 and subsequent nuclear export of the TERF2IP-TERF2 complex. In this study, we investigated TERF2IP-dependent gene expression and its role in regulating d-flow-induced SASP.MethodsA principal component analysis and hierarchical clustering were used to identify genes whose expression is regulated by TERF2IP in ECs under d-flow conditions. Senescence was determined by reduced telomere length, increased p53 and p21 expression, and increased apoptosis; EC activation was detected by NF-κB activation and the expression of adhesion molecules. The involvement of TERF2IP S205 phosphorylation in d-flow-induced SASP was assessed by depletion of TERF2IP and mutation of the phosphorylation site.ResultsOur unbiased transcriptome analysis showed that TERF2IP caused alteration in the expression of a distinct set of genes, including rapamycin-insensitive companion of mTOR (RICTOR) and makorin-1 (MKRN1) ubiquitin E3 ligase, under d-flow conditions. In particular, both depletion of TERF2IP and overexpression of the TERF2IP S205A phosphorylation site mutant in ECs increased the d-flow and p90RSK-induced MKRN1 expression and subsequently inhibited apoptosis, telomere shortening, and NF-κB activation in ECs via suppression of p53, p21, and telomerase (TERT) induction.ConclusionsMKRN1 and RICTOR belong to a distinct reciprocal gene set that is both negatively and positively regulated by p90RSK. TERF2IP S205 phosphorylation, a downstream event of p90RSK activation, uniquely inhibits MKRN1 expression and contributes to EC activation and senescence, which are key events for atherogenesis.

Dataset Information

Single-cell transcriptomics identifies senescence-associated secretory phenotype (SASP) features of testicular aging in human.

Publications

Single-cell transcriptomics identifies senescence-associated secretory phenotype (SASP) features of testicular aging in human.

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