Characterization of a non-human primate model for the study of testicular peritubular cells—comparison with human testicular peritubular cells

Schmid, Nina; Stöckl, Jan B.; Flenkenthaler, Florian; Dietrich, Kim-Gwendolyn; Schwarzer, Julia; Köhn, Frank-Michael; Drummer, Charis; Fröhlich, Thomas; Arnold, Georg J.; Behr, Rüdiger; Mayerhofer, Artur

doi:10.1093/molehr/gay025

Cited by 14 publications

(20 citation statements)

References 19 publications

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“…While the availability of donated human testicular material is limited, human organoids are of great interest for their utility in studies of human health. Macaques provide a valuable model closely related to humans [23][24][25][26], although both practical and ethical considerations can limit tissue supplies. With their greater availability and long history, mouse models have proved informative [10,27,28], although with substantial differences in scale and reproductive strategies, Discoveries in rodent models often fail to translate to humans [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Formation of organotypic testicular organoids in microwell culture†

Sakib

Uchida

Valenzuela-Leon

et al. 2019

Biology of Reproduction

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Three-dimensional (3D) organoids can serve as an in vitro platform to study cell–cell interactions, tissue development, and toxicology. Development of organoids with tissue architecture similar to testis in vivo has remained a challenge. Here, we present a microwell aggregation approach to establish multicellular 3D testicular organoids from pig, mouse, macaque, and human. The organoids consist of germ cells, Sertoli cells, Leydig cells, and peritubular myoid cells forming a distinct seminiferous epithelium and interstitial compartment separated by a basement membrane. Sertoli cells in the organoids express tight junction proteins claudin 11 and occludin. Germ cells in organoids showed an attenuated response to retinoic acid compared to germ cells in 2D culture indicating that the tissue architecture of the organoid modulates response to retinoic acid similar to in vivo. Germ cells maintaining physiological cell–cell interactions in organoids also had lower levels of autophagy indicating lower levels of cellular stress. When organoids were treated with mono(2-ethylhexyl) phthalate (MEHP), levels of germ cell autophagy increased in a dose-dependent manner, indicating the utility of the organoids for toxicity screening. Ablation of primary cilia on testicular somatic cells inhibited the formation of organoids demonstrating an application to screen for factors affecting testicular morphogenesis. Organoids can be generated from cryopreserved testis cells and preserved by vitrification. Taken together, the testicular organoid system recapitulates the 3D organization of the mammalian testis and provides an in vitro platform for studying germ cell function, testicular development, and drug toxicity in a cellular context representative of the testis in vivo.

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Section: Introductionmentioning

confidence: 99%

Formation of organotypic testicular organoids in microwell culture†

Sakib

Uchida

Valenzuela-Leon

et al. 2019

Biology of Reproduction

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“…The cells were either fixed with 3.7 % formaldehyde and immediately stained or transfected with SIRT1 siRNA and fixed 72 h after transfection. The fixed cells were washed, permeabilized, counterstained with DAPI and mounted, as described previously [41]. The antibodies were diluted in 0.1 % Triton X-100/PBS + 5 % goat normal serum, SIRT1 at 4 µg/mL (Atlas Antibody, HPA006295) and SIRT3 at 1:100 (Santa Cruz, sc-365175, Dallas, TX, USA).…”

Section: Immunofluorescencementioning

confidence: 99%

Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors

Schmid¹,

Dietrich²,

Forné³

et al. 2021

IJMS

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Sirtuins (SIRTs) are NAD+-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1–7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs in situ, these SIRTs may represent novel drug targets.

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“…Second, isolating Sertoli or Leydig cells is generally a time-consuming and very delicate process that also necessitates the availability of fresh tissue, complex enzymatic digestion steps of the seminiferous tubules, followed by segregation of the various cells using flow cytometry and adhesion purification techniques such as DSA-lectin or gradient centrifugation. Moreover, with spermatogonial stem cells (SSCs) culture being essential to male infertility therapy in humans [206], endangered species preservation, and transgenic animal technology, isolation of these cells have been exhaustively described in the literature [206,207,208,209,210,211,212,213,214], though the survival of these cells beyond 48 to 96 hours in culture is challenging [211,212,215] as they require continuous hormonal or co-culture stimulation. Additionally, identifying the various cells before culture can prove challenging [207,208,210,212,213,216,217], thus many adopt marker-assisted selection following culture, though this technique only reports a percentage of each cell type in the culture.…”

Section: Challenges To the Study Of The Effect Of Mycotoxins On Mamentioning

confidence: 99%

Updates on the Effect of Mycotoxins on Male Reproductive Efficiency in Mammals

Khoury

Fayjaloun

Nassar

et al. 2019

Toxins

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Mycotoxins are ubiquitous and unavoidable harmful fungal products with the ability to cause disease in both animals and humans, and are found in almost all types of foods, with a greater prevalence in hot humid environments. These mycotoxins vary greatly in structure and biochemical effects; therefore, by better understanding the toxicological and pathological aspects of mycotoxins, we can be better equipped to fight the diseases, as well as the biological and economic devastations, they induce. Multiple studies point to the association between a recent increase in male infertility and the increased occurrence of these mycotoxins in the environment. Furthermore, understanding how mycotoxins may induce an accumulation of epimutations during parental lifetimes can shed light on their implications with respect to fertility and reproductive efficiency. By acknowledging the diversity of mycotoxin molecular function and mode of action, this review aims to address the current limited knowledge on the effects of these chemicals on spermatogenesis and the various endocrine and epigenetics patterns associated with their disruptions.

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Characterization of a non-human primate model for the study of testicular peritubular cells—comparison with human testicular peritubular cells

Abstract: This work was supported by grants from the Deutsche Forschungsgemeinschaft (MA 1080/27-1; AR 362/9-1; BE 2296/8-1). The authors declare no competing financial interests.

Cited by 14 publications

References 19 publications

Formation of organotypic testicular organoids in microwell culture†

Formation of organotypic testicular organoids in microwell culture†

Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors

Updates on the Effect of Mycotoxins on Male Reproductive Efficiency in Mammals

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