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Single-cell analysis of human testis aging and correlation with elevated body mass index

ABSTRACT: Aging human males display reduced reproductive health, however testis aging is poorly understood at the molecular and genomic level. Here, we utilized single-cell RNA-seq to profile over 44,000 cells from both young and older men (>60 years old) – and examined age-related changes in germline development and in the somatic niche. Interestingly, age-related changes in spermatogonial stem cells appeared modest, whereas age-related dysregulation of spermatogenesis and the somatic niche ranged from moderate to severe. Altered pathways included signaling and inflammation in multiple cell types, metabolic signaling in Sertoli cells, hedgehog signaling and testosterone production in Leydig cells, cell death and growth in testicular peritubular cells, and possible developmental regression in both Leydig and peritubular cells. Remarkably, the extent of dysregulation correlated with body mass index in older, but not younger men. Taken together, we reveal candidate molecular mechanisms underlying the complex testicular changes conferred by aging, and their exacerbation by concurrent chronic conditions such as obesity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182786 | GEO | 2022/05/05

REPOSITORIES: GEO

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Project description:Aging of the human testis and associated cellular changes are difficult to assess, thus we used a translational non-human primate model to get insights into underlying biochemical processes. Using proteomics we analyzed testicular tissue of six young (age 2 to 3) and four old (age 10 to 12) C. jacchus individuals. Mass spectrometry identified 63124 peptides, which could be assigned to 5924 proteins. Among them we found proteins, which are specific for germ cells, Leydig cells, and somatic cells, indicating the relevance of the dataset. The quantitative analysis showed 31 differentially abundant proteins, of which 29 proteins were more abundant in old animals. An increased abundance of several anti-proliferative proteins, among them CDKN2A, indicate slowed cell proliferation in older testes. Immunohistochemistry localized CDKN2A in spermatogonia and spermatocytes, suggesting altered spermatogenesis. Additionally, an increased abundance of several extracellular proteins and small leucine rich repeat proteoglycans was observed, which may be related to impaired cell migration and fibrotic events. An increased abundance of proteins with inhibitory roles in smooth muscle cell contraction like CNN1, indicate functional alterations, specifically in peritubular cells and may mirror a reduced capacity of these cells, to contract in aged testes. In summary, these results document several age-associated changes in the testicular proteome of a non-human primate model and provides new insight into testicular aging.

2021-06-21 | PXD024844 | Pride

Proteomic insights into senescence of testicular peritubular cells from a nonhuman primate model

Project description:Age-related changes of the human testis may include morphological alterations, disturbed steroidogenesis and impaired spermatogenesis. However, the specific impact of cell age remains poorly understood and difficult to assess. Testicular peritubular cells fulfill essential functions, including sperm transport, contributions to the spermatogonial stem cell niche and paracrine interactions within the testis. To study their role in age-associated decline of testicular functions, we performed comprehensive proteome and secretome analyses of repeatedly passaged peritubular cells from Callithrix jacchus. This nonhuman primate model better reflects the human testicular biology than rodents and further gives access to young donors unavailable from humans. Among 5095 identified proteins, 583 were differentially abundant between samples with low and high passage numbers. The alterations indicate a reduced ability of senescent peritubular cells to contract and secrete proteins, as well as disturbances in NF-κB signaling and a reduced capacity to handle reactive oxygen species. Since this in vitro model may not exactly mirror all molecular aspects of in vivo aging, we investigated the proteomes and secretomes of testicular peritubular cells from young and old donors. Even though the age-related alterations at the protein level were less pronounced, we found evidence for impaired protein secretion, altered NF-κB signaling and reduced contractility of these in vivo aged peritubular cells.

2020-11-18 | PXD022165 | Pride

Characterization of a nonhuman primate model for the study of testicular peritubular cells – comparison with human testicular cells

Project description:Smooth-muscle-like peritubular cells make up the wall of semniferous tubules of men. These human testicular peritubular cells (HTPC) have been shown to fulfill different roles. They transport sperm, secrete various factors like GDNF (glial cell line derived neurotrophic factor) and are immunologically active. They might contribute to spermatogonial stem cell niche altering and testicular ageing. Previous studies were limited regarding heterogeneity (due to lifestyle, age, medical history etc.) and accessibility of HTPCs. To circumvent this problem a cellular primate model should be established. The proteome of 6 MKTPCs of individual healthy and young (2 or 3 years) donors was assessed to investigate the suitability as a model.

2018-06-06 | PXD009394 | Pride

The molecular signature of human testicular peritubular cells revealed by single-cell analysis

Project description:Peritubular cells of the human testis form a small compartment surrounding the seminiferous tubules. It contrast to rodents, it is composed of several cell layers and extracellular matrix. Peritubular cells are crucial for sperm transport and emerge as contributors to the spermatogonial stem cell niche, yet testicular peritubular cells are among the least known cell types of the human body. We employed single-cell RNA sequencing of cultured human testicular peritubular cells (HTPCs) isolated from testicular samples of donors with normal spermatogenesis and compared our data with recently published ex vivo data and, if available, with immunohistochemical data of the Human Protein Atlas. We observed a significant overlap between our results and genes expressed in vivo. Based on expression of a set of smooth muscle markers, HTPCs can be classified as smooth muscle cells. Small differences between in vivo/in vitro expressed genes may be due to plasticity/phenotypic switching. Plasticity was also shown upon addition of FCS to the culture medium. Based on transcriptome similarities four cellular states were observed. Characteristics of mesenchymal stromal cells and Leydig stem cells were noted, yet differentiation attempts into fat cells, bone cells or mature Leydig cells were not successful. Further analyses confirmed known stem cell niche-relevant factors (e.g. GDNF) and identified unknown functions e.g. the ability to produce retinoic acid. The results reveal that HTPCs upon isolation and culture are a highly adequate cellular model as they retain major characteristics. They therefore allow us to define the signature and functions of human testicular peritubular cells. The data may serve as a resource for future studies to better understand male (in)fertility.

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Project description:In addition to germ cell population, testes contain several types of somatic cells, including Sertoli cells, Leydig cells, and peritubular myoid (PTM) cells. PTM cells are a type of smooth muscle-like cells and have contraction ability. To identify a marker of PTM cells, we isolated primary cells and subsequently performed RNA-Seq of testicular peritubular myoid cells (PTM_1, PTM_2, PTM_3), testicular Sertoli cells (Sertoli_1, Sertoli_2, Sertoli_3), testicular Leydig cells (Leydig_1, Leydig_2, Leydig_3), testicular germ cells (Germ_1, Germ_2, Germ_3), vascular smooth muscle cells (VSMC_1, VSMC_2, VSMC_3), intestinal smooth muscle cells (ISMC_1, ISMC_2, ISMC_3), and tracheal smooth muscle cells (TSMC_1, TSMC_2, TSMC_3) using BGISEQ-500 platform (BGI, China).

2019-01-19 | GSE125303 | GEO

miRNA-Seq of testicular peritubular myoid cells, other testicular cells, and other tissue smooth muscle-like cells

Project description:In addition to germ cell population, testes contain several types of somatic cells, including Sertoli cells, Leydig cells, and peritubular myoid (PTM) cells. PTM cells are a type of smooth muscle-like cells and have contraction ability. To identify a marker of PTM cells, we isolated primary cells and subsequently performed miRNA-Seq of testicular peritubular myoid cells (PTM_1, PTM_2, PTM_3), testicular Sertoli cells (Sertoli_1, Sertoli_2, Sertoli_3), testicular Leydig cells (Leydig_1, Leydig_2, Leydig_3), testicular germ cells (Germ_1, Germ_2, Germ_3), vascular smooth muscle cells (VSMC_1, VSMC_2, VSMC_3), intestinal smooth muscle cells (ISMC_1, ISMC_2, ISMC_3), and tracheal smooth muscle cells (TSMC_1, TSMC_2, TSMC_3) using BGISEQ-500 platform (BGI, China).

2019-01-19 | GSE125302 | GEO

Single-cell Transcriptome Atlas of Testis Aging

Project description:Unhealthy aging of testis seriously affects fertility and life quality of older men, while its interventions depend on in-depth knowledge of the molecular and functional changes of various testicular cell types. Here, we profile human testicular single-cell transcriptomes from young adult, healthy old men and late-onset hypogonadism (LOH) patients, and identified the somatic cells underwent a greater change than germ cells.

2022-10-17 | GSE215754 | GEO

Leptin secreted from testicular microenvironment modulates hedgehog signaling to augment the endogenous function of Leydig cells

Project description:Although testosterone deficiency (TD) may be present in 1 out of 5 men 40 years or older, the factors responsible for TD remain largely unknown. Leydig stem cells (LSCs) differentiate into adult Leydig cells (ALC) and produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from the pituitary gland. However, recent studies have suggested that the testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells (PMC), plays an instrumental role in LSC differentiation and testosterone production under the regulation of the desert hedgehog signaling pathway (DHH). It was hypothesized that TME releases paracrine factors to modulate LSC differentiation. For this purpose, cells (Sertoli, PMCs, LSCs and ALCs) were extracted from men undergoing testis biopsies for sperm retrieval and were evaluated for the paracrine factors in the presence or absence of TME (Sertoli and PMC). The results demonstrated that TME secretes leptin which induces LSC differentiation and increases T production. Leptin’s effects on LSC differentiation and T production, however, are inversely concentration-dependent: positive at low doses and negative at higher doses. Mechanistically, leptin acts on LSCs upstream of DHH; leptin-DHH regulation functions unidirectionally insofar as DHH gain or loss of function has no effects on leptin levels. Taken together, these findings identify leptin as a key paracrine factor released by cells within the TME that modulates LSC differentiation and testosterone release from mature Leydig cells, a finding with important clinical implications for TD.

2022-02-17 | GSE196702 | GEO

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