Immune and vascular contributions to organogenesis of the testis and ovary

Gu, Xu; Li, Shuyun; DeFalco, Tony

doi:10.1111/febs.15848

Cited by 23 publications

(29 citation statements)

References 217 publications

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“…While rodent primitive macrophages are first seen in gonadal primordium, as early as E10.5 in mice, fetal rat macrophages have been observed in testis starting at GD16 to 19. Rodent fetal testicular macrophages express mainly M2 polarization-type markers and are believed to be important for maternal-fetal tolerance ( Meinhardt et al, 2018 ; Gu et al, 2021 ). The numbers of macrophages increase slowly until the onset of puberty, where macrophages rapidly increase and decline thereafter.…”

Section: Fetal and Neonatal Male Reproductive Development In Rodents ...mentioning

confidence: 99%

“…The numbers of macrophages increase slowly until the onset of puberty, where macrophages rapidly increase and decline thereafter. During puberty, testicular macrophages interact intimately with Leydig cells through digitations or microvillus-like processes that are inserted within coated pits of the macrophages ( Hutson 1990 ; Hutson 1992 ; Plant and Zeleznik 2014 ; Gu et al, 2021 ).…”

Section: Fetal and Neonatal Male Reproductive Development In Rodents ...mentioning

confidence: 99%

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Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Tran-Guzman

Culty

2022

Front. Toxicol.

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Increasing rates of infertility associated with declining sperm counts and quality, as well as increasing rates of testicular cancer are contemporary issues in the United States and abroad. These conditions are part of the Testicular Dysgenesis Syndrome, which includes a variety of male reproductive disorders hypothesized to share a common origin based on disrupted testicular development during fetal and neonatal stages of life. Male reproductive development is a highly regulated and complex process that relies on an intricate coordination between germ, Leydig, and Sertoli cells as well as other supporting cell types, to ensure proper spermatogenesis, testicular immune privilege, and endocrine function. The eicosanoid system has been reported to be involved in the regulation of fetal and neonatal germ cell development as well as overall testicular homeostasis. Moreover, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics with abilities to block eicosanoid synthesis by targeting either or both isoforms of cyclooxygenase enzymes, have been found to adversely affect male reproductive development. This review will explore the current body of knowledge on the involvement of the eicosanoid system in male reproductive development, as well as discuss adverse effects of NSAIDs and analgesic drugs administered perinatally, focusing on toxicities reported in the testis and on major testicular cell types. Rodent and epidemiological studies will be corroborated by findings in invertebrate models for a comprehensive report of the state of the field, and to add to our understanding of the potential long-term effects of NSAID and analgesic drug administration in infants.

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Section: Fetal and Neonatal Male Reproductive Development In Rodents ...mentioning

confidence: 99%

Section: Fetal and Neonatal Male Reproductive Development In Rodents ...mentioning

confidence: 99%

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Tran-Guzman

Culty

2022

Front. Toxicol.

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“…The testis is a significant immune-sparing site that protects immunogenic germ cells from adverse effects of the immune response ( 14 ). Both local immunosuppression and systemic immune responses may be involved in maintaining testicular immunity ( 15 ). Pattern recognition receptors (PRRs) play a significant role in the testicular innate immune response.…”

Section: Testicular Immunitymentioning

confidence: 99%

Varicocele-Mediated Male Infertility: From the Perspective of Testicular Immunity and Inflammation

Fang

et al. 2021

Front. Immunol.

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BackgroundVaricocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system.ResultsThe testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB).ConclusionsThe testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.

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“…In the XY gonads at E12.5, the mesonephric vascular plexus breaks down releasing the mesonephric endothelial cells which migrate into the testis establishing a vascular network and forming a coelomic blood vessel (Coveney et al, 2008; Svingen and Koopman, 2013; Ungewitter and Yao, 2013). Signalling factors like Fgfs, Pdgf , and Vegf aid in endothelial migration and male-specific blood vascular patterning (Cool et al, 2011; Gu et al, 2021; Svingen and Koopman, 2013). Vascularization is crucial for the delivery of exogenous factors in the testicular compartments, in the initial organization of the testis cords, and also in the regulation of testis morphogenesis (Gu et al, 2021; Singh and Modi, 2020; Svingen and Koopman, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Signalling factors like Fgfs, Pdgf , and Vegf aid in endothelial migration and male-specific blood vascular patterning (Cool et al, 2011; Gu et al, 2021; Svingen and Koopman, 2013). Vascularization is crucial for the delivery of exogenous factors in the testicular compartments, in the initial organization of the testis cords, and also in the regulation of testis morphogenesis (Gu et al, 2021; Singh and Modi, 2020; Svingen and Koopman, 2013). It is also required for maintaining the interstitial progenitor population of the fetal Leydig cells (Gu et al, 2021; Kumar and DeFalco, 2018; Li et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Lhx2 in germ cells suppresses endothelial cell migration in the developing ovary

Singh

Bhide

et al. 2022

Preprint

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LIM-homeobox genes play multiple roles in developmental processes, but their roles in gonad development are not completely understood. Herein, we report that Lhx2, Ils2, Lmx1a, and Lmx1b are expressed in a sexually dimorphic manner in mouse, rat, and human gonads during sex determination. Amongst these, Lhx2 has female biased expression in the developing gonads of species with environmental and genetic modes of sex determination. Single-cell RNAseq analysis revealed that Lhx2 is exclusively expressed in the germ cells of the developing mouse ovaries. To elucidate the roles of Lhx2 in the germ cells, we analyzed the phenotypes of Lhx2 knockout XX gonads. While the gonads developed appropriately in Lhx2 knockout mice and the somatic cells were correctly specified in the developing ovaries, transcriptome analysis revealed enrichment of genes in the angiogenesis pathway. There was an elevated expression of several pro-angiogenic factors in the Lhx2 knockout ovaries. The elevated expression of pro-angiogenic factors was associated with an increase in numbers of endothelial cells in the Lhx2-/- ovaries at E13.5. Gonad recombination assays revealed that the increased numbers of endothelial cells in the XX gonads in absence of Lhx2 was due to ectopic migration of endothelial cells in a cell non-autonomous manner. We also found that, there was increased expression of several endothelial cell-enriched male-biased genes in Lhx2 knockout ovaries. Also, in absence of Lhx2, the migrated endothelial cells formed an angiogenic network similar to that of the wild type testis, although the coelomic blood vessel did not form. Together, our results suggest that Lhx2 in the germ cells is required to suppress vascularization in the developing ovary. These results suggest a need to explore the roles of germ cells in the control of vascularization in developing gonads.

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Immune and vascular contributions to organogenesis of the testis and ovary

Abstract: contributed equally to this work.

Cited by 23 publications

References 217 publications

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs

Varicocele-Mediated Male Infertility: From the Perspective of Testicular Immunity and Inflammation

Lhx2 in germ cells suppresses endothelial cell migration in the developing ovary

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