Stem Leydig cells: Current research and future prospects of regenerative medicine of male reproductive health

Li, Xiaoheng; Tian, Erpo; Wang, Yiyan; Zhu, Wen; Lei, Z; Zhong, Ying

doi:10.1016/j.semcdb.2021.05.007

Cited by 26 publications

(24 citation statements)

References 84 publications

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“…SLCs are capable of proliferating and differentiating into functional LCs, playing an important role in maintaining the number of LCs and intratesticular environmental homeostasis 18 . Thus, to determine whether the shrinkage in LC colonies is caused by dysfunction in generating new LCs, we tracked the cell fate of Nestin-expressing SLCs by labeling them with RFP (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing

et al. 2022

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Male reproductive system ageing is closely associated with deficiency in testosterone production due to loss of functional Leydig cells, which are differentiated from stem Leydig cells (SLCs). However, the relationship between SLC differentiation and ageing remains unknown. In addition, active lipid metabolism during SLC differentiation in the reproductive system requires transportation and processing of substrates among multiple organelles, e.g., mitochondria and endoplasmic reticulum (ER), highlighting the importance of interorganelle contact. Here, we show that SLC differentiation potential declines with disordered intracellular homeostasis during SLC senescence. Mechanistically, loss of the intermediate filament Nestin results in lower differentiation capacity by separating mitochondria-ER contacts (MERCs) during SLC senescence. Furthermore, pharmacological intervention by melatonin restores Nestin-dependent MERCs, reverses SLC differentiation capacity and alleviates male reproductive system ageing. These findings not only explain SLC senescence from a cytoskeleton-dependent MERCs regulation mechanism, but also suggest a promising therapy targeting SLC differentiation for age-related reproductive system diseases.

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Section: Resultsmentioning

confidence: 99%

Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing

et al. 2022

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“…Understanding the cellular components of the human testis is of importance for the understanding of the testis, male fertility and infertility. Furthermore, with regard to male hypogonadism, such insights are required to guide regenerative medicine [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

The Molecular Signature of Human Testicular Peritubular Cells Revealed by Single-Cell Analysis

Liebich

Schmid

Koupourtidou

et al. 2022

Cells

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Peritubular cells of the human testis form a small compartment surrounding the seminiferous tubules. They are crucial for sperm transport, and they emerge as contributors to the spermatogonial stem cell niche. They are among the least known cell types of the human body. We employed single-cell RNA sequencing of cultured human testicular peritubular cells (HTPCs), which had been isolated from testicular samples of donors with normal spermatogenesis. The significant overlap between our results and recently published ex vivo data indicates that HTPCs are a highly adequate cellular model to define and study these cells. Thus, based on the expression of several markers, HTPCs can be classified as testicular smooth muscle cells. Small differences between the in vivo/in vitro expressed genes may be due to cellular plasticity. Plasticity was also shown upon addition of FCS to the culture medium. Based on transcriptome similarities, four cellular states were identified. Further analyses confirmed the presence of known stem cell niche-relevant factors (e.g., GDNF) and identified unknown functions, e.g., the ability to produce retinoic acid. Therefore, HTPCs allow us to define the signature(s) and delineate the functions of human testicular peritubular cells. The data may also serve as a resource for future studies to better understand male (in)fertility.

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“…Two independent LC generations develop consecutively in the testis: Fetal (FLCs) and adult Leydig cells (ALCs). FLCs differentiate from progenitor pool of precursor cells, which are spindle‐shaped and located near seminiferous tubules 16 . FLCs make androgens to promote the development of the male reproductive tract.…”

Section: Introductionmentioning

confidence: 99%

“…FLCs differentiate from progenitor pool of precursor cells, which are spindle-shaped and located near seminiferous tubules. 16 FLCs make androgens to promote the development of the male reproductive tract. FLCs also make insulin-like 3 peptide hormone (INSL3) to induce initial transabdominal migration of fetal testes.…”

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confidence: 99%

Tetramethyl bisphenol A stimulates proliferation but inhibits fetal Leydig cell function in male rats by targeting estrogen receptor α after in utero exposure

Meng

et al. 2022

Environmental Toxicology

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Tetramethyl bisphenol A (TMBPA) is a widely used flame retardant. TMBPA has been a toxic to Leydig cells in puberty, but it remains unclear whether TMBPA has a similar inhibitor effect on fetal Leydig cells (FLCs). This study reported morphological and functional alterations of FLCs in the testes of male offspring at birth after in utero exposure to TMBPA. Pregnant Sprague Dawley rats were dosed via continuous gavage of TMBPA (0, 10, 50, and 200 mg/kg/day) from gestational day 14 to 21. TMBPA markedly raised serum total testosterone level, testicular volume, and FLC number of male offspring at 200 mg/kg dose. The up‐regulation of Insl3, Star, and Cyp11a1 mRNAs was observed after 200 mg/kg TMBPA exposure. After normalization to the number of FLCs, TMBPA significantly reduced Lhcgr and Hsd3b1 expressions at 10 mg/kg, and Cyp17a1 at 200 mg/kg paralleling with their protein levels. TMBPA compromised the expression of Esr1, while increased the expression of Cdk2 and Cdk4 as well as their protein levels. TMBPA particularly increased the phosphorylation of AKT1 and AKT2 at 200 mg/kg. In conclusion, the present study suggests that TMBPA may promote FLC proliferation via ESR1‐CDK2/4‐AKT pathway, while inhibits the function of FLCs by reducing steroidogenic enzyme activity.

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Stem Leydig cells: Current research and future prospects of regenerative medicine of male reproductive health

Cited by 26 publications

References 84 publications

Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing

Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing

The Molecular Signature of Human Testicular Peritubular Cells Revealed by Single-Cell Analysis

Tetramethyl bisphenol A stimulates proliferation but inhibits fetal Leydig cell function in male rats by targeting estrogen receptor α after in utero exposure

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