A Novel Organoid Model of In Vitro Spermatogenesis Using Human Induced Pluripotent Stem Cells

Robinson, Meghan; Witherspoon, Luke; Willerth, Stephanie M.; Flannigan, Ryan

doi:10.1101/2021.06.04.447122

“…These data are strong circumstantial evidence that relaxed selection in these genes in gorillas may have adverse consequences for male reproductive function. A potential solution to this limitation is genome editing in iPSC and organoid models of spermatogenesis; however these models, although promising, do not yet generate mature functional sperm in vitro (Easley et al, 2012; Hayashi et al, 2011; Robinson et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

Bowman,

Silva,

Schüftan

et al. 2023

Preprint

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Gorillas have a polygynous social system in which the highest-ranking male has almost exclusive access to females and sires most of the offspring in the troop. Such behavior results in a dramatic reduction of sperm competition, which is ultimately associated with numerous traits that cause low efficacy of gorilla spermatogenesis. However, the molecular basis behind the remarkable erosion of the gorilla male reproductive system remains unknown. Here, we explored the genetic consequences of the polygynous social system in gorillas by testing for altered selection intensity across 13,310 orthologous protein-coding genes from 261 Eutherian mammals. We identified 578 genes with relaxed purifying selection in the gorilla lineage, compared with only 96 that were positively selected. Genes under relaxed purifying selection in gorillas have accumulated numerous deleterious amino acid substitutions, their expression is biased towards male germ cells, and are enriched in functions related to meiosis and sperm biology. We tested the function of gorilla relaxed genes previously not implicated in sperm biology using the Drosophila model system and identified 41 novel spermatogenesis genes required for normal fertility. Furthermore, by exploring exome/genome sequencing data of infertile men with severe spermatogenic impairment, we found that the human orthologs of the gorilla relaxed genes are enriched for loss-of-function variants in infertile men. These data provide compelling evidence that reduced sperm competition in gorillas is associated with relaxed purifying selection on genes related to male reproductive function. The accumulation of deleterious mutations in these genes likely provides the mechanistic basis behind the low efficacy of gorilla spermatogenesis and uncovers new candidate genes for human male infertility.

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“…In one of these studies, various testicular cell types including spermatogonia, Leydig, peritubular myoid, and endothelial cells were derived from human iPSCs using cell-line specific 2D culture media conditions. Resulting cells were then co-cultured as organoids, leading to formation of tubular structures, mature somatic cell, and post-meiotic gametes ( Robinson et al, 2021 ). Ultimately the promise of restored fertility has also occurred with the application of iPSCs in an animal model.…”

Section: De Novo Generation Of Testicular Parenchymal Cellsmentioning

confidence: 99%

De novo testicular tissue generation from non-testicular cell lines, biologic and synthetic scaffolds: Current findings and future translational applications

Hosseini

¹

,

DeBenedetto

²

,

Jiang

³

et al. 2022

Front. Cell Dev. Biol.

2

0

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In recent decades, reproductive science has revolutionized the options for biological parenthood for the 20–50% of infertility cases affected by male factors. However, current solutions exclude those who are infertile due to absent testicular tissue. This includes anorchic 46, XY individuals due to trauma or congenital factors and transgender men with a 46, XX genotype. There is a clinical need for methods to restore testicular function independent of pre-existing testicular tissue. This mini-review analyzes studies that have applied non-testicular cell lines to generate germline and non-germline testicular parenchymal components. While only 46, XY cell lines have been evaluated in this context to date, the potential for future application of cell lines from 46, XX individuals is also included. Additionally, the role of varied culture methods, media supplementation, and biologic and synthetic scaffolds to further support testicular parenchyma generation are critiqued. De novo testicular tissue generation in this manner will require a focus on both cellular and environmental aspects of tissue engineering. Put together, these studies highlight the future potential for expanded clinical, reproductive, and endocrine management options for individuals who are currently excluded from aspects of biologic reproduction most consistent with their gender identity and reproductive preferences.

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Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

Bowman,

Silva,

Schüftan

et al. 2024

Preprint

1

0

View full text Add to dashboard Cite

Gorillas have a polygynous social system in which the highest-ranking male has almost exclusive access to females and sires most of the offspring in the troop. Such behavior results in a dramatic reduction of sperm competition, which is ultimately associated with numerous traits that cause low efficacy of gorilla spermatogenesis. However, the molecular basis behind the remarkable erosion of the gorilla male reproductive system remains unknown. Here, we explored the genetic consequences of the polygynous social system in gorillas by testing for altered selection intensity across 13,310 orthologous protein-coding genes from 261 Eutherian mammals. We identified 578 genes with relaxed purifying selection in the gorilla lineage, compared with only 96 that were positively selected. Genes under relaxed purifying selection in gorillas have accumulated numerous deleterious amino acid substitutions, their expression is biased towards male germ cells, and are enriched in functions related to meiosis and sperm biology. We tested the function of gorilla relaxed genes previously not implicated in sperm biology using the Drosophila model system and identified 41 novel spermatogenesis genes required for normal fertility. Furthermore, by exploring exome/genome sequencing data of infertile men with severe spermatogenic impairment, we found that the human orthologs of the gorilla relaxed genes are enriched for loss-of-function variants in infertile men. These data provide compelling evidence that reduced sperm competition in gorillas is associated with relaxed purifying selection on genes related to male reproductive function. The accumulation of deleterious mutations in these genes likely provides the mechanistic basis behind the low efficacy of gorilla spermatogenesis and uncovers new candidate genes for human male infertility.

show abstract

A Novel Organoid Model of In Vitro Spermatogenesis Using Human Induced Pluripotent Stem Cells

Cited by 4 publications

References 83 publications

Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

De novo testicular tissue generation from non-testicular cell lines, biologic and synthetic scaffolds: Current findings and future translational applications

Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

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