Origin and regulation of stem Leydig cells in the adult testis

Chen, Panpan; Zhao, Xingxing; Guan, Xiaoju; Chen, Haolin

doi:10.1016/j.coemr.2019.03.002

Cited by 4 publications

(6 citation statements)

References 36 publications

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“…Similar to the findings in earlier reports ( Ge et al , 2006 ; Jiang et al , 2014 ), transplanted RFP-labelled endosialin + cells colonized the testicular interstitium and differentiated into functional LCs. Beyond that, we observed that the transplanted cells homed to a specific location in which SLCs usually reside ( Li et al , 2016 ; Kumar and DeFalco, 2018 ; Chen et al , 2020 ) and that they were perfused by host vessels, forming an organic whole ( Chong et al , 2014 ). Additionally, the majority of endosialin + cells retained characteristics of stem cells, as indicated by the expression of the putative SLCs markers endosialin and PDGFRα, which had not been examined for SLCs in previous studies.…”

Section: Discussionmentioning

confidence: 93%

“…Meanwhile, the testosterone production of the transplanted cells was not as high as those in vitro , in accordance with the low differentiation ratio in vivo determined by immunofluorescence assays. A possible explanation for this finding is that the microenvironment in 3-week-old mouse testes was not perfect for the differentiation of human SLCs since SLCs commit to a differentiation pathway to form LCs lineages by postpartum day 11 in mice ( Ye et al , 2017 ; Chen et al , 2020 ). Surprisingly, although the transplanted endosialin + cells survived and exhibited measurable cell cycle activity, the retrieved RFP-labelled cells accounted for only 10% of the total transplanted cells 4 weeks after transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…To the best of our knowledge, several cell types besides SLCs have been proposed to differentiate into adults LCs, as follows. First, previous studies have provided evidence that pericytes are the progenitors of the LCs in the testes ( Davidoff et al , 2004 ; Chen et al , 2019 ; Davidoff, 2019 ). In the present study, the self-renewal and differentiation properties of endosialin + human SLCs were highly similar to the characteristics of pericytes ( Armulik et al , 2011 ; Wong et al , 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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Endosialin defines human stem Leydig cells with regenerative potential

Xia

Feng

et al. 2020

Human Reproduction

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STUDY QUESTION Is endosialin a specific marker of human stem Leydig cells (SLCs) with the ability to differentiate into testosterone-producing Leydig cells (LCs) in vitro and in vivo? SUMMARY ANSWER Endosialin is a specific marker of human SLCs which differentiate into testosterone-producing LCs in vitro and in vivo. WHAT IS KNOWN ALREADY Human SLCs have been identified and isolated using the marker platelet-derived growth factor receptor α (PDGFRα) or nerve growth factor receptor (NGFR). However, the specificity was not high; thus, LCs and germ cells could be mistakenly sorted as SLCs if PDGFRα or NGFR was used as a marker for human SLCs isolation. STUDY DESIGN, SIZE, DURATION Firstly, we re-evaluated the specificity of PDGFRα and NGFR for SLCs in adult human testes. Then we analysed the previously published single-cell sequencing data and found that endosialin may identify human SLCs. Subsequently, we sorted endosialin+ cells from four human donors and characterized their self-renewal and multipotent properties. To assess whether endosialin+ cells have the potential to differentiate into functional LCs in vitro, these cells were stimulated by differentiation-inducing medium. We next assessed the in vivo regenerative potential of human endosialin+ cells after xenotransplantation into the testes of immunodeficient mice. PARTICIPANTS/MATERIALS, SETTING, METHODS Single-cell sequencing analysis, immunofluorescence and flow cytometry were used to characterize human testis tissues. In vitro colony formation, multipotent differentiation (adipogenic, osteogenic and chondrogenic) and Leydig cell-lineage induction were used to assess stem cell activity. Xenotransplantation into 3-week-old immunodeficient mice was used to determine in vivo regenerative potential. Endpoint measures included testosterone measurements, cell proliferation, immunofluorescence, flow cytometry and quantitative RT–PCR. MAIN RESULTS AND THE ROLE OF CHANCE The results indicate that endosialin is a specific marker of SLCs compared with PDGFRα and NGFR. Additionally, endosialin+ cells isolated from human testes show extensive proliferation and differentiation potential in vitro: their self-renewal ability was inferred by the formation of spherical clones derived from a single cell. Moreover, these cells could differentiate into functional LCs that secreted testosterone in response to LH in a concentration-dependent manner in vitro. These self-renewal and differentiation properties reinforce the proposal that human testicular endosialin+ cells are SLCs. Furthermore, transplanted human endosialin+ cells appear to colonize the murine host testes, localize to peritubular and perivascular regions, proliferate measurably and differentiate partially into testosterone-producing LCs in vivo. LARGE SCALE DATA NA. LIMITATIONS, REASONS FOR CAUTION Owing to the difficulty in collecting human testis tissue, the sample size was limited. The functions of endosialin on SLCs need to be elucidated in future studies. WIDER IMPLICATIONS OF THE FINDINGS A discriminatory marker, endosialin, for human SLCs purification is a prerequisite to advance research in SLCs and logically promote further clinical translation of SLCs-based therapies for male hypogonadism. STUDY FUNDING/COMPETING INTEREST(S) A.P.X. was supported by the National Key Research and Development Program of China (2017YFA0103802 and 2018YFA0107200). C.D. was supported by the National Natural Science Foundation of China (81971314) and the Natural Science Foundation of Guangdong Province, China (2018B030311039). The authors declare no conflict of interest.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Endosialin defines human stem Leydig cells with regenerative potential

Xia

Feng

et al. 2020

Human Reproduction

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“…Hormones promote the pathophysiology of schizophrenia by increasing local dopamine synthesis and metabolism ( Salilew-Wondim et al, 2015 ; Chen et al, 2019 ). Besides, many hormones affect the movement behavior of organisms, such as epilepsy, depression, etc.…”

Section: Discussionmentioning

confidence: 99%

Attractin Participates in Schizophrenia by Affecting Testosterone Levels

Gao

Wang

et al. 2021

Front. Cell Dev. Biol.

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Attractin (ATRN) is a widely expressed glycoprotein that is involved in energy homeostasis, neurodevelopment, and immune response. It is encoded by a gene spanning 180 kb on chromosome 20p13, a region previously implicated in schizophrenia by linkage studies. To address a possible role of ATRN in disorders of the central nervous system, we created an atrn knockout zebrafish line and performed behavioral tests. Adult atrn–/– zebrafish exhibited more pronounced attack behavior relative to wild-type control zebrafish in a tracking analysis. Biochemical analysis revealed elevated testosterone levels in atrn–/– zebrafish. At the gene expression level, we noted an upregulation of cyp51 and hsd17b7, key proteins in testosterone synthesis in the brains of both adult and larvae of atrn–/– zebrafish. In order to further elucidate the relationship between testosterone and behavioral syndromes, we then compared testosterone levels of 9,008 psychiatric patients and 247 healthy controls from the same catchment area. Of all subjects examined, male subjects with schizophrenia exhibited lower testosterone levels compared with controls. In contrast, female subjects with a diagnosis of schizophrenia or bipolar disorder featured higher testosterone levels than did same sex controls. Purposeful sampling of extreme groups showed reduced ATRN expression in a subset of these subjects. Finally, we identified 14 subjects with ATRN mutations. All of whom displayed abnormal testosterone levels. In summary, the interplay of ATRN and testosterone may help to explain sexual dimorphisms in selected behavioral phenotypes.

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“… 104 , 105 Thus, these scRNA‐seq analyses suggest that the TCF21+ mesenchymal cell population includes stem Leydig cells, a progenitor of adult Leydig cells. 106 Although whether PTMs have mesonephric or gonadal cell origin remains controversial, 107 these scRNA‐seq analyses support that PTMs are derived from gonadal interstitial progenitor cells. Consistent with the mouse scRNA‐seq analyses, human Leydig and myeloid cells were suggested to be derived from the same progenitor population.…”

Section: Single‐cell Transcriptomics In Spermatogenesismentioning

confidence: 95%

Overview of single‐cell RNA sequencing analysis and its application to spermatogenesis research

Suzuki

2023

Reprod Medicine & Biology

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Background Single‐cell transcriptomics allows parallel analysis of multiple cell types in tissues. Because testes comprise somatic cells and germ cells at various stages of spermatogenesis, single‐cell RNA sequencing is a powerful tool for investigating the complex process of spermatogenesis. However, single‐cell RNA sequencing analysis needs extensive knowledge of experimental technologies and bioinformatics, making it difficult for many, particularly experimental biologists and clinicians, to use it. Methods Aiming to make single‐cell RNA sequencing analysis familiar, this review article presents an overview of experimental and computational methods for single‐cell RNA sequencing analysis with a history of transcriptomics. In addition, combining the PubMed search and manual curation, this review also provides a summary of recent novel insights into human and mouse spermatogenesis obtained using single‐cell RNA sequencing analyses. Main Findings Single‐cell RNA sequencing identified mesenchymal cells and type II innate lymphoid cells as novel testicular cell types in the adult mouse testes, as well as detailed subtypes of germ cells. This review outlines recent discoveries into germ cell development and subtypes, somatic cell development, and cell–cell interactions. Conclusion The findings on spermatogenesis obtained using single‐cell RNA sequencing may contribute to a deeper understanding of spermatogenesis and provide new directions for male fertility therapy.

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Origin and regulation of stem Leydig cells in the adult testis

Cited by 4 publications

References 36 publications

Endosialin defines human stem Leydig cells with regenerative potential

Endosialin defines human stem Leydig cells with regenerative potential

Attractin Participates in Schizophrenia by Affecting Testosterone Levels

Overview of single‐cell RNA sequencing analysis and its application to spermatogenesis research

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