Three populations of adult Leydig cells in mouse testes revealed by a novel mouse HSD3B1-specific rat monoclonal antibody

Yokoyama, Chikako; Chigi, Yuta; Baba, Takashi; Ohshitanai, Atsushi; Harada, Yumi; Takahashi, Fumiya; Morohashi, Ken Ichirou

doi:10.1016/j.bbrc.2019.02.100

Cited by 19 publications

(12 citation statements)

References 18 publications

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“…There are reports that Leydig cell heterogeneity may exist in the adult testis ( Yokoyama et al, 2019 ), including the presence of fetal Leydig cells ( Shima, et al, 2015 ). To examine whether any of the three Leydig cell sub-groups detected in the current study have fetal Leydig cell characteristics, the top 200 enriched genes of the three groups were compared to published mouse ( Sararols et al, 2021 ) and human ( Lottrup et al, 2017 ) fetal and adult Leydig cell markers.…”

Section: Resultsmentioning

confidence: 99%

Identification of Rat Testicular Leydig Precursor Cells by Single-Cell-RNA-Sequence Analysis

Guan

Chen

et al. 2022

Front. Cell Dev. Biol.

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Stem Leydig cells (SLCs) play a critical role in the development and maintenance of the adult Leydig cell (ALC) population. SLCs also are present in the adult testis. Their identification, characteristics, and regulation in the adult testis remain uncertain. Using single-cell RNA-seq, we found that the mesenchymal stromal population may be involved in ALC regeneration. Upon ALC elimination, a fraction of stromal cells begins to proliferate while a different fraction begins to differentiate to ALCs. Transcriptomic analysis identified five stromal clusters that can be classified into two major groups representing proliferation and differentiation populations. The proliferating group represents stem cells expressing high levels of CD90, Nes, Lum, Fn and Gap43. The differentiating group represents a progenitor stage that is ready to form ALCs, and specifically expresses Vtn, Rasl11a, Id1 and Egr2. The observation that the actively dividing cells after ALC loss were not those that formed ALCs suggests that stem cell proliferation and differentiation are regulated separately, and that the maintenance of the stromal stem cell pool occurs at the population level. The study also identified specific markers for the major interstitial cell groups and potential paracrine factors involved in the regulation of SLCs. Our data suggest a new theory about SLC identity, proliferation, differentiation, and regulation.

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Section: Resultsmentioning

confidence: 99%

Identification of Rat Testicular Leydig Precursor Cells by Single-Cell-RNA-Sequence Analysis

Guan

Chen

et al. 2022

Front. Cell Dev. Biol.

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“…1 ). Interestingly, these analyses also revealed that FADS2 was highly expressed in Leydig cells (labeled with an antibody against HSD3B1 15 ), the cells responsible for androgen production (Fig. 1c and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 82%

Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production

Lee-Okada

Yokomizo

2022

Commun Biol

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Highly unsaturated fatty acids (HUFAs) are fatty acids with more than three double bonds in the molecule. Mammalian testes contain very high levels of omega-6 HUFAs compared with other tissues. However, the metabolic and biological significance of these HUFAs in the mammalian testis is poorly understood. Here we show that Leydig cells vigorously synthesize omega-6 HUFAs to facilitate male sex hormone production. In the testis, FADS2 (Fatty acid desaturase 2), the rate-limiting enzyme for HUFA biosynthesis, is highly expressed in Leydig cells. In this study, pharmacological and genetic inhibition of FADS2 drastically reduces the production of omega-6 HUFAs and male steroid hormones in Leydig cells; this reduction is significantly rescued by supplementation with omega-6 HUFAs. Mechanistically, hormone-sensitive lipase (HSL; also called LIPE), a lipase that supplies free cholesterol for steroid hormone production, preferentially hydrolyzes HUFA-containing cholesteryl esters as substrates. Taken together, our results demonstrate that Leydig cells highly express FADS2 to facilitate male steroid hormone production by accumulating omega-6 HUFA-containing cholesteryl esters, which serve as preferred substrates for HSL. These findings unveil a previously unrecognized importance of omega-6 HUFAs in the mammalian male reproductive system.

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“…First, qRT-PCR indicated a significant decrease of Insl3 expression, another marker gene for Leydig cells ( 63 , 64 ), in Start -KO testes at 8 dpp but not in adults ( Supplemental Figure 3A ). Second, the expression of Hsd3b6 , a marker gene for adult Leydig cells ( 65 ), showed no difference between wild-type and Start -KO testes in adults ( Supplemental Figure 3B ). These results indicated that the number of Leydig cells was decreased in Start -KO mice at 8 dpp.…”

Section: Resultsmentioning

confidence: 99%

A Testis-Specific Long Noncoding RNA, Start, Is a Regulator of Steroidogenesis in Mouse Leydig Cells

et al. 2021

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The testis expresses many long noncoding RNAs (lncRNAs), but their functions and overview of lncRNA variety are not well understood. The mouse Prss/Tessp locus contains six serine protease genes and two lncRNAs that have been suggested to play important roles in spermatogenesis. Here, we found a novel testis-specific lncRNA, Start (Steroidogenesis activating lncRNA in testis), in this locus. Start is 1822 nucleotides in length and was found to be localized mostly in the cytosol of germ cells and Leydig cells, although nuclear localization was also observed. Start-knockout (KO) mice generated by the CRISPR/Cas9 system were fertile and showed no morphological abnormality in adults. However, in adult Start-KO testes, RNA-seq and qRT-PCR analyses revealed an increase in the expression of steroidogenic genes such as Star and Hsd3b1, while ELISA analysis revealed that the testosterone levels in serum and testis were significantly low. Interestingly, at 8 days postpartum, both steroidogenic gene expression and testosterone level were decreased in Start-KO mice. Since overexpression of Start in two Leydig-derived cell lines resulted in elevation of the expression of steroidogenic genes including Star and Hsd3b1, Start is likely to be involved in their upregulation. The increase in expression of steroidogenic genes in adult Start-KO testes might be caused by a secondary effect via the androgen receptor autocrine pathway or the hypothalamus-pituitary-gonadal axis. Additionally, we observed a reduced number of Leydig cells at 8 days postpartum. Collectively, our results strongly suggest that Start is a regulator of steroidogenesis in Leydig cells. The current study provides an insight into the overall picture of the function of testis lncRNAs.

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Three populations of adult Leydig cells in mouse testes revealed by a novel mouse HSD3B1-specific rat monoclonal antibody

Cited by 19 publications

References 18 publications

Identification of Rat Testicular Leydig Precursor Cells by Single-Cell-RNA-Sequence Analysis

Identification of Rat Testicular Leydig Precursor Cells by Single-Cell-RNA-Sequence Analysis

Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production

A Testis-Specific Long Noncoding RNA, Start, Is a Regulator of Steroidogenesis in Mouse Leydig Cells

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