Single-cell analysis of the developing human testis reveals somatic niche cell specification and fetal germline stem cell establishment

Guo, Jingtao; Sosa, Enrique; Chitiashvili, Tsotne; Nie, Xiaolu; Rojas, Ernesto J.; Oliver, Elizabeth; DonorConnect,; Plath, Kathrin; Hotaling, James M.; Stukenborg, Jan-Bernd; Clark, Amander T.; Cairns, Bradley R.

doi:10.1016/j.stem.2020.12.004

Cited by 145 publications

(180 citation statements)

References 44 publications

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“…S1e – 1j ). Based on the expression of the marker genes RGS5 and TPM2 we assigned the stromal (STRO) cluster to pericytes 17 , 18 or vascular smooth muscle cells according to the expression of FABP4 19 , 20 (Fig. 1c ; Supplementary information, Fig.…”

Section: Resultsmentioning

confidence: 99%

Aging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia

et al. 2021

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Molecular mechanisms associated with human germ cell aplasia in infertile men remain undefined. Here we perform single-cell transcriptome profiling to highlight differentially expressed genes and pathways in each somatic cell type in testes of men with idiopathic germ cell aplasia. We identify immaturity of Leydig cells, chronic tissue inflammation, fibrosis, and senescence phenotype of the somatic cells, as well markers of chronic inflammation in the blood. We find that deregulated expression of parentally imprinted genes in myoid and immature Leydig cells, with relevant changes in the ratio of Lamin A/C transcripts and an active DNA damage response in Leydig and peritubular myoid cells are also indicative of senescence of the testicular niche. This study offers molecular insights into the pathogenesis of idiopathic germ cell aplasia.

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Section: Resultsmentioning

confidence: 99%

Aging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia

et al. 2021

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“…However, deep analyses of the numerous isoforms and sexual comparative analysis remain in the to-do list. The current race to single cell and/or spatial RNAseq analysis may also, in the near future, provide a better understanding of the dynamics of the expression of proteins of the steroidogenic pathway and of their possible isoform specificities and may highlight cell specificities in the steps of cell lineage [98,99].…”

Section: Steroidogenic Fingerprintsmentioning

confidence: 99%

“…Single cell RNAseq allowed the tracing of the lineage of interstitial progenitors for Leydig cells from the early steps of differentiation up to postnatal life. The identification of markers for each step of differentiation and of species specificities compared with mice [99] also resulted; however, this study was focused on the testis, leaving the ovary in a state of comparative darkness in this respect.…”

Section: Steroidogenic Fingerprintsmentioning

confidence: 99%

Six Decades of Research on Human Fetal Gonadal Steroids

Connan-Perrot

Léger

Lelandais

et al. 2021

IJMS

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Human fetal gonads acquire endocrine steroidogenic capabilities early during their differentiation. Genetic studies show that this endocrine function plays a central role in the sexually dimorphic development of the external genitalia during fetal development. When this endocrine function is dysregulated, congenital malformations and pathologies are the result. In this review, we explain how the current knowledge of steroidogenesis in human fetal gonads has benefited from both the technological advances in steroid measurements and the assembly of detailed knowledge of steroidogenesis machinery and its expression in human fetal gonads. We summarise how the conversion of radiolabelled steroid precursors, antibody-based assays, mass spectrometry, ultrastructural studies, and the in situ labelling of proteins and mRNA have all provided complementary information. In this review, our discussion goes beyond the debate on recommendations concerning the best choice between the different available technologies, and their degrees of reproducibility and sensitivity. The available technologies and techniques can be used for different purposes and, as long as all quality controls are rigorously employed, the question is how to maximise the generation of robust, reproducible data on steroid hormones and their crucial roles in human fetal development and subsequent functions.

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“…Recent advances in single cell genomics enable the examination of thousands of individual cells, including those of entire organs without the need for prior sorting or enrichment procedures. Work from several groups has proven the power of single cell RNA-seq (scRNA-seq) profiling to study human testis development and pathology (Guo et al, 2017(Guo et al, , 2018(Guo et al, , 2020(Guo et al, , 2021Sohni et al, 2019;Shami et al, 2020;Wang and Xu, 2020). Here, we continue to leverage our unique sample resource (involving rapid autopsy testis samples from cadaveric organ donors) to apply scRNAseq and other approaches such as immunostaining.…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Analysis of Human Testis Aging, and Impact of Elevated Body Mass Index

Nie

Munyoki

Sukhwani

et al. 2021

Preprint

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SUMMARYAging 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.

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Single-cell analysis of the developing human testis reveals somatic niche cell specification and fetal germline stem cell establishment

Cited by 145 publications

References 44 publications

Aging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia

Aging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia

Six Decades of Research on Human Fetal Gonadal Steroids

Single-Cell Analysis of Human Testis Aging, and Impact of Elevated Body Mass Index

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