Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells

Zhao, Liangyu; Yao, Chencheng; Xing, Xiaoyu; Tao, Jing; Li, Peng; Zhu, Zijue; Yang, Chao; Zhai, Jing; Tian, Ruhui; Chen, HuiXing; Luo, Jianwen; Liu, Nachuan; Deng, ZhiWen; Lin, Xiaohong; Li, Na; Fang, Jing; Sun, Jie; Wang, Chenchen; Zhou, Zhi

doi:10.1038/s41467-020-19414-4

Cited by 159 publications

(220 citation statements)

References 32 publications

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“… 29 Tan et al listed most of the single‐cell transcriptome analyses that have been conducted on mouse, human, and macaque testes 30 . By modifying their report, single‐cell transcriptome analysis performed using human testicular samples is summarized in Table 1, 31–38 which included eight publications and our current project. The majority of them have focused on germ cells, and the major method to isolate and harvest a single cell type, which is the most important and difficult part of single‐cell analysis, was enzymatic digestion combined with flow cytometric sorting or physical filtering.…”

Section: Single Cell Analysis Of Testicular Cellsmentioning

confidence: 99%

Genome medicine in male infertility: From karyotyping to single‐cell analysis

Shiraishi

2021

J of Obstet and Gynaecol

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Male infertility is a multifactorial pathological condition that affects half of infertile couples. The majority of cases are categorized as idiopathic, especially in cases of nonobstructive azoospermia (NOA). An increasing number of genetic abnormalities have been shown to cause spermatogenic impairment with the development of microarray technologies and next‐generation sequencing (NGS), moving beyond classical karyotype and polymerase chain reaction analyses of targeted genes. However, the majority of gene mutations, such as Klinefelter syndrome, azoospermia factor microdeletion, or congenital bilateral absence of the vas deferens, fail to function in a one gene‐one phenotype manner. Single‐cell transcriptome analysis performed using human testicular samples has begun to be published, which has brought about a more comprehensive understanding of testicular pathology. NGS also enables omics approaches, which provide more powerful tools to interrogate the genome, epigenome, transcriptome, and proteome. Simultaneously, the involvement of environmental factors and comorbidities, which may potentially regulate epigenetic factors, has been shown, resulting in a more complex understanding of the pathophysiology of spermatic disorders, especially NOA. The combination of phenotypic data and large amounts of bioinformatical data obtained by NGS may provide a more comprehensive understanding of the pathophysiology of male infertility, which will contribute not only to a diagnosis but also to the proper selection of infertility treatment and the development of new treatment modalities for male infertility.

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Section: Single Cell Analysis Of Testicular Cellsmentioning

confidence: 99%

Genome medicine in male infertility: From karyotyping to single‐cell analysis

Shiraishi

2021

J of Obstet and Gynaecol

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“…Currently, except for traditional microarray analysis, several studies have used weighted gene co-expression network analysis (WGCNA) analysis [ 14 ], whole-exome sequencing [ 15 ], and single-cell transcriptome sequencing (scRNA-seq) [ 16 , 17 ] to screen for novel infertility causative genes in NOA. The resulting data provide a basis for further studies on the pathogenesis of NOA, but these existing studies do not integrate multiple sequencing data, which makes the results obtained by a single analytical approach less convincing.…”

Section: Introductionmentioning

confidence: 99%

“…Since its development, single-cell transcriptome sequencing has been widely used in cancer and bio-developmental fields with excellent results. Although two studies performed single-cell transcriptome sequencing on testicular tissue from NOA patients [ 16 , 17 ], no study has yet applied these open resources to an integrated analysis of NOA; this omission lays the foundation for our study.…”

Section: Introductionmentioning

confidence: 99%

Infertility network and hub genes for nonobstructive azoospermia utilizing integrative analysis

Han

Yan

et al. 2021

Aging

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Non-obstructive azoospermia (NOA) is the most severe form of male infertility owing to the absence of sperm during ejaculation as a result of failed spermatogenesis. The molecular mechanisms of NOA have not been well studied. Here, we revealed the dysregulated differentially expressed genes in NOA and related signaling pathways or biological processes. Cluster features of biological processes include spermatogenesis, fertilization, cilium movement, penetration of zona pellucida, sperm chromatin condensation, and being significantly enriched metabolic pathways in proximal tubule bicarbonate reclamation, aldosterone synthesis and secretion, glycolysis and glycogenesis pathways in NOA using Gene Ontology analysis and pathway enrichment analysis. The NOA gene co-expression network was constructed by weighted gene co-expression network analysis to identify the hub genes ( CHD5 and SPTBN2 ). In addition, we used another Gene Expression Omnibus dataset (GSE45887) to validate these hub genes. Furthermore, we used the Seurat package to classify testicular tissue cells from NOA patients and to characterize the differential expression of hub genes in different cell types from different adult males based on the scRNA-seq dataset (GSE106487). These results provide new insights into the pathogenesis of NOA. Of particular note, CHD5 and SPTBN2 may be potential biomarkers for the diagnosis and treatment of NOA.

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“…[1] Pinpointing the causes of infertility therefore requires an understanding of the cellular niche where sperm are generated. Advances in single cell sequencing of testicular tissue have begun to shed light on the transcriptomic signatures of the cell types within the niche, [2][3][4][5][6][7][8] however the development of in vitro tools to study their interactions and functionalities remains elusive. [9] Historically, animal models have been the standard in modeling human diseases, however there are specifically human biological processes such as infertility whose complexity and interindividual variability cannot be accurately modeled using animals.…”

Section: Introductionmentioning

confidence: 99%

A Novel Organoid Model of In Vitro Spermatogenesis Using Human Induced Pluripotent Stem Cells

Robinson¹,

Witherspoon

Willerth

et al. 2021

Preprint

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Infertility is thought to be caused by genetic mutations and dysfunction in the cellular niche where spermatogenesis takes place. An understanding of the specialized cellular processes which drive spermatogenesis is needed to develop treatments; however, the development of in vitro systems to study these cells has been hindered by our reliance on rarely available human testicular tissues for research. Human induced pluripotent stem cells (hiPSCs) can be used to derive human testicular-like cells, and thus provide an avenue for the development of in vitro testicular model systems. Therefore, this study set out to engineer a human testicular tissue model using hiPSCs for the first time. We demonstrate the ability of hiPSC-derived testicular cells to self-organize and mature into testicular-like tissues using organoid culture. Moreover, we show that hiPSC-derived testicular organoids promote testicular somatic cell maturation and spermatogenesis up to the post-meiotic spermatid stage. These hiPSC-derived testicular organoids have the potential to replace rarely available primary testicular tissues to further infertility research in an in vitro setting.

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Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells

Cited by 159 publications

References 32 publications

Genome medicine in male infertility: From karyotyping to single‐cell analysis

Genome medicine in male infertility: From karyotyping to single‐cell analysis

Infertility network and hub genes for nonobstructive azoospermia utilizing integrative analysis

A Novel Organoid Model of In Vitro Spermatogenesis Using Human Induced Pluripotent Stem Cells

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