Sterile inflammation as a factor in human male infertility: Involvement of Toll like receptor 2, biglycan and peritubular cells

Mayer, Christine; Adam, Marion; Glashauser, L.; Dietrich, Kim-Gwendolyn; Schwarzer, Julia; Köhn, F.-M.; Strauss, Leena; Welter, Harald; Poutanen, Matti; Mayerhofer, Artur

doi:10.1038/srep37128

Cited by 50 publications

(66 citation statements)

References 47 publications

(90 reference statements)

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“…Since the response to tissue injury is often context dependent, it is important to understand what signaling pathways may influence key decisions such as fibrosis vs. regeneration. We show that in the testis Tcf21 has regenerative potential; while other have observed fibrosis in the testes of men with impaired spermatogenesis, and fibrosis is historically regarded as a hallmark of infertility (Adashi et al, 1996;Frungieri et al, 2002a;Frungieri et al, 2002b;Mayer et al, 2016;Meineke et al, 2000). However, whether dysregulation of the Tcf21 + population may be involved in the pathogenesis of infertility remains to be examined.…”

Section: Discussionmentioning

confidence: 58%

Tcf21⁺mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration

Shen

Larose

Shami

et al. 2020

Preprint

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2 Highlights • Multipotent Tcf21 + MPs can differentiate into somatic testis cell types • Tcf21 + cells contribute to testis and ovary somatic cells during gonadal development • Tcf21 + cells replenish somatic cells of the aging testis and in response to tissue injury • Testis Tcf21 cells resemble resident fibroblast populations in multiple organs 3 Summary Testicular development and function relies on interactions between somatic cells and the germline, but similar to other organs, regenerative capacity decline in aging and disease. Whether the adult testis maintains a reserve progenitor population with repair or regenerative capacity remains uncertain. Here, we characterized a recently identified mouse testis interstitial population expressing the transcription factor Tcf21. We found that Tcf21 + cells are bipotential somatic progenitors present in fetal testis and ovary, maintain adult testis homeostasis during aging, and act as reserve somatic progenitors following injury. In vitro, Tcf21 + cells are multipotent mesenchymal progenitors which form multiple somatic lineages including Leydig and myoid cells. Additionally, Tcf21 + cells resemble resident fibroblast populations reported in other organs having roles in tissue homeostasis, fibrosis, and regeneration. Our findings reveal that the testis, like other organs, maintains multipotent mesenchymal progenitors that can be leveraged in development of future therapies for hypoandrogenism and/or infertility.

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Section: Discussionmentioning

confidence: 58%

Tcf21⁺mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration

Shen

Larose

Shami

et al. 2020

Preprint

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“…In addition to proteins that are present at lower levels in AROM+ animals we also detect factors that are significantly upregulated upon aromatase overexpression. Most of these have been shown to be involved in the regulation of the extracellular matrix similar to what has been shown upon an upregulation of pro-inflammatory pathways (Adam, Urbanski et al, 2012, Li et al, 2006, Mayer, Adam et al, 2016, Walenta, Schmid et al, 2018.…”

Section: Discussionmentioning

confidence: 70%

Imaging mass spectrometry and shotgun proteomics reveal dysregulated pathways in hormone induced male infertility

Lahiri¹,

Valenta²,

Aftab³

et al. 2020

Preprint

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ABBREVIATIONS MALDI-IMS -Matrix assisted laser desorption/ionisation imaging mass spectrometry LC-MS -Liquid chromatography mass spectrometry WT -Wild type AROM+ -Mice overexpressing human P450 aromatase E2/T -Estrogen/Testosterone ratio ECM -Extracellular matrix ER -Endoplasmic reticulum GO -Gene ontology UPR -Unfolded protein response AbstractSpermatogenesis is a complex multi-step process involving intricate interactions between different cell types in the male testis. Disruption of these interactions results in infertility.Combination of shotgun tissue proteomics with MALDI imaging mass spectrometry is markedly potent in revealing topological maps of molecular processes within tissues. Here, we use a combinatorial approach on a characterized mouse model of hormone induced male infertility to uncover misregulated pathways. Comparative testicular proteome of wildtype and mice overexpressing human P450 aromatase (AROM+) with pathologically increased estrogen levels unravels gross dysregulation of spermatogenesis and emergence of proinflammatory pathways in AROM+ testis. In situ MS allowed us to localize misregulated proteins/peptides to defined regions within the testis. Results suggest that infertility is associated with substantial loss of proteomic heterogeneity, which define distinct stages of seminiferous tubuli in healthy animals. Importantly, considerable loss of mitochondrial factors, proteins associated with late stages of spermatogenesis and steroidogenic factors characterise AROM+ mice. Thus, the novel proteomic approach pinpoints in unprecedented ways the disruption of normal processes in testis and provides a signature for male infertility.

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“…Other proteins, including BGN or PTX3, which were implicated in immunological roles of HTPCs (Mayer et al ., ), were not statistically significantly affected.…”

Section: Discussionmentioning

confidence: 73%

“…However, TPCs are also secretory cells and some of these products, namely ECM components, are involved in structural functions. Other products, for example growth factors, are capable to modulate testicular functions, including immune functions and spermatogenesis (Schell et al ., ; Spinnler et al ., ; Mayerhofer, ; Flenkenthaler et al ., ; Welter et al ., ; Mayer et al ., ). Specifically, human TPCs (HTPCs), as well as TPCs of mice, produce and constitutively release glial cell line‐derived neurotrophic factor (GDNF)( Spinnler et al ., ; Chen et al ., , ).…”

Section: Introductionmentioning

confidence: 97%

Insights into the role of androgen receptor in human testicular peritubular cells

et al. 2018

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Contractile smooth muscle-like peritubular cells build the wall of seminiferous tubules in men. They are crucial for sperm transport and complement the functions of Sertoli cells by secreting factors, including glial cell line-derived neurotrophic factor. Previous studies revealed that they also secrete the chemokine C-X-C motif chemokine ligand 12 (CXCL12), which has known roles in spermatogenesis. Peritubular cells express the androgen receptor (AR), which is retained in isolated human testicular peritubular cells. We aimed to explore AR-regulated functions in human testicular peritubular cells. Bearing in mind that infertile men often have high aromatase activity, which may lower intratesticular androgen concentrations, an animal model for male infertility was studied. These mice display an age-dependent loss in spermatogenesis due to high aromatase activity. Human testicular peritubular cells were exposed to dihydrotestosterone or the antiandrogen flutamide. We studied AR, smooth muscle cell markers, glial cell line-derived neurotrophic factor and 15 secreted factors previously identified, including CXCL12. We used qPCR, Western blotting, ELISA or selected reaction monitoring (SRM). In the animal model for male infertility, we employed qPCR and immunohistochemistry. Dihydrotestosterone increased AR and flutamide prevented these actions. The smooth muscle cell markers calponin and smooth muscle actin were likewise increased, while cell size or cellular proliferation was not changed. Dihydrotestosterone did not increase glial cell line-derived neurotrophic factor or CXCL12 secretion but increased levels of serine proteinase inhibitor (SERPIN) E1. The animal model for male infertility with high aromatase activity showed reduced numbers of AR-immunoreactive testicular peritubular cells, suggesting that altered androgen and/or oestrogen levels could influence AR-mediated responses in peritubular cells. Androgens act on human testicular peritubular cells to enhance AR levels, their contractile phenotype and to modulate the secretion of some secreted factors. This study suggests that some aspects of human peritubular cell functions are regulated by androgens.

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Sterile inflammation as a factor in human male infertility: Involvement of Toll like receptor 2, biglycan and peritubular cells

Cited by 50 publications

References 47 publications

Tcf21⁺mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration

Tcf21⁺mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration

Imaging mass spectrometry and shotgun proteomics reveal dysregulated pathways in hormone induced male infertility

Insights into the role of androgen receptor in human testicular peritubular cells

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Sterile inflammation as a factor in human male infertility: Involvement of Toll like receptor 2, biglycan and peritubular cells

Cited by 50 publications

References 47 publications

Tcf21+mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration

Tcf21+mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration

Imaging mass spectrometry and shotgun proteomics reveal dysregulated pathways in hormone induced male infertility

Insights into the role of androgen receptor in human testicular peritubular cells

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Tcf21⁺mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration

Tcf21⁺mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration