Generation of ovarian follicles from mouse pluripotent stem cells

Yoshino, Takashi; Suzuki, Tsuyoshi; Nagamatsu, Go; Yabukami, Haruka; Ikegaya, Mika; Kishima, Mami; Kita, Haruka; Imamura, Takuya; Nakashima, Kinichi; Nishinakamura, Ryuichi; Tachibana, Makoto; Inoue, Miki; Shima, Yuichi; Morohashi, Ken Ichirou; Hayashi, Kozaburo

doi:10.1126/science.abe0237

Cited by 92 publications

(71 citation statements)

References 44 publications

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“…However, all of these culture systems require matched somatic cells, which are obtained from embryos at E12.5. Yoshino et al reported that fetal gonadal somatic-like cells can be induced from ESCs [ 41 ]. Our data complemented the findings of Yoshino et al, demonstrating that fetal gonadal somatic-like cells can be induced by only two small molecules from ESCs, which function to promote meiosis induction and progression.…”

Section: Discussionmentioning

confidence: 99%

“…However, to construct a successful platform for elucidating the molecular mechanisms underlying meiosis and oocyte production, developmentally matched gonadal somatic cells are indispensable. These cells have only been obtained from E12.5 female gonads [ 33 ], until a recent breakthrough [ 41 ]. Moreover, the embryo destruction required for obtaining these cells is not feasible in humans.…”

Section: Introductionmentioning

confidence: 99%

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Induction of meiosis by embryonic gonadal somatic cells differentiated from pluripotent stem cells

et al. 2021

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Background Depletion of oocytes leads to ovarian aging-associated infertility, endocrine disruption and related diseases. Excitingly, unlimited oocytes can be generated by differentiation of primordial germ cell like cells (PGCLCs) from pluripotent stem cells. Nevertheless, development of oocytes and follicles from PGCLCs relies on developmentally matched gonadal somatic cells, only available from E12.5 embryos in mice. It is therefore imperative to achieve an in vitro source of E12.5 gonadal somatic cells. Methods We explored to identify small molecules, which can induce female embryonic stem cells (ESCs) into gonadal somatic cell like cells. Results Using RNA-sequencing, we identified signaling pathways highly upregulated in E12.5_gonadal somatic cells (E12.5_GSCs). Through searching for the activators of these pathways, we identified small-molecule compounds Vitamin C (Vc) and AM580 in combination (V580) for inducing differentiation of female embryonic stem cells (ESCs) into E12.5_GSC-like cells (E12.5_GSCLCs). After V580 treatment for 6 days and sorted by a surface marker CD63, the cell population yielded a transcriptome profile similar to that of E12.5_GSCs, which promoted meiosis progression and folliculogenesis of primordial germ cells. This approach will contribute to the study of germ cell and follicle development and oocyte production and have implications in potentially treating female infertility. Conclusion ESCs can be induced into embryonic gonadal somatic cell like cells by small molecules.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of meiosis by embryonic gonadal somatic cells differentiated from pluripotent stem cells

et al. 2021

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“…The induction of iPSCs into primordial germ cells like cells (PGCs-like cells or PGCLCs) opened a new possibility to investigate the specification of germ cells, helping to understand the main events of their development [30,31]. Over the last few years, the field of PGCLCs is progressing so rapidly that recent studies have shown the possibility of inducing human PGCLCs in oogonia-like and pro-spermatogonia-like cells [32][33][34]; although the generation of in vitro germ cells with robust and long-term reconstitution potential still remains a significant challenge. In vitro germ cell-like cells (GCLCs) of TS have been reported via xenotransplantation into murine seminiferous tubules [35].…”

Section: Introductionmentioning

confidence: 99%

Generation of Primordial Germ Cell-like Cells from iPSCs Derived from Turner Syndrome Patients

Souza

Bressan

Pieri

et al. 2021

Cells

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Turner syndrome (TS) is a genetic disorder in females with X Chromosome monosomy associated with highly variable clinical features, including premature primary gonadal failure leading to ovarian dysfunction and infertility. The mechanism of development of primordial germ cells (PGCs) and their connection with ovarian failure in TS is poorly understood. An in vitro model of PGCs from TS would be beneficial for investigating genetic and epigenetic factors that influence germ cell specification. Here we investigated the potential of reprogramming peripheral mononuclear blood cells from TS women (PBMCs-TS) into iPSCs following in vitro differentiation in hPGCLCs. All hiPSCs-TS lines demonstrated pluripotency state and were capable of differentiation into three embryonic layers (ectoderm, endoderm, and mesoderm). The PGCLCs-TS recapitulated the initial germline development period regarding transcripts and protein marks, including the epigenetic profile. Overall, our results highlighted the feasibility of producing in vitro models to help the understanding of the mechanisms associated with germ cell formation in TS.

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“…Ovarian aging is a complex biological process influenced by the interaction and gradual accumulation of internal and external factors [ 1 , 2 ], which can lead to a decline in estrogen levels, a shortened menstrual cycle, and a decrease in female reproductive capacity until the final menopause. It can also lead to a series of menopausal symptoms caused by endocrine disorders, such as cardiovascular diseases, osteoporosis, and obesity [ 3 , 4 , 5 , 6 , 7 , 8 ], which seriously affect women’s physical and mental health and quality of life. However, the commonly used clinical diagnostic indicators such as follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH) each have advantages and disadvantages [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Physiological Ovarian Aging Is Associated with Altered Expression of Post-Translational Modifications in Mice

Wei

Yan

et al. 2021

IJMS

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Post-translational modifications (PTMs) have been confirmed to be involved in multiple female reproductive events, but their role in physiological ovarian aging is far from elucidated. In this study, mice aged 3, 12 or 17 months (3M, 12M, 17M) were selected as physiological ovarian aging models. The expression of female reproductive function-related genes, the global profiles of PTMs, and the level of histone modifications and related regulatory enzymes were examined during physiological ovarian aging in the mice by quantitative real-time PCR and western blot, respectively. The results showed that the global protein expression of Kbhb (lysineβ-hydroxybutyryllysine), Khib (lysine 2-hydroxyisobutyryllysine), Kglu (lysineglutaryllysine), Kmal (lysinemalonyllysine), Ksucc (lysinesuccinyllysine), Kcr (lysinecrotonyllysine), Kbu (lysinebutyryllysine), Kpr (lysinepropionyllysine), SUMO1 (SUMO1 modification), ub (ubiquitination), P-Typ (phosphorylation), and 3-nitro-Tyr (nitro-tyrosine) increased significantly as mice aged. Moreover, the modification level of Kme2 (lysinedi-methyllysine) and Kac (lysineacetyllysine) was the highest in the 3M mice and the lowest in 12M mice. In addition, only trimethylation of histone lysine was up-regulated progressively and significantly with increasing age (p < 0.001), H4 ubiquitination was obviously higher in the 12M and 17M mice than 3M (p < 0.001), whereas the modification of Kpr (lysinepropionylation) and O-GlcNA in 17M was significantly decreased compared with the level in 3M mice (p < 0.05, p < 0.01). Furthermore, the expression levels of the TIP60, P300, PRDM9, KMT5B, and KMT5C genes encoding PTM regulators were up-regulated in 17M compared to 3M female mice (p < 0.05). These findings indicate that altered related regulatory enzymes and PTMs are associated with physiological ovarian aging in mice, which is expected to provide useful insights for the delay of ovarian aging and the diagnosis and treatment of female infertility.

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Generation of ovarian follicles from mouse pluripotent stem cells

Cited by 92 publications

References 44 publications

Induction of meiosis by embryonic gonadal somatic cells differentiated from pluripotent stem cells

Induction of meiosis by embryonic gonadal somatic cells differentiated from pluripotent stem cells

Generation of Primordial Germ Cell-like Cells from iPSCs Derived from Turner Syndrome Patients

Physiological Ovarian Aging Is Associated with Altered Expression of Post-Translational Modifications in Mice

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