Reconstitution of mouse oogenesis in a dish from pluripotent stem cells

Hayashi, Kozaburo; Hikabe, Orie; Obata, Yayoi; Hirao, Yuji

doi:10.1038/nprot.2017.070

Cited by 65 publications

(55 citation statements)

References 26 publications

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“…IVDi Culture. IVDi culture was performed as described (7). rOvaries (containing 2,500 PGCLCs and 37,500 gonadal somatic cells or 5,000 PGCLCs and 75,000 gonadal somatic cells) were placed on Transwell-COL membranes and cultured under the normoxic condition (20% O 2 and 5% CO 2 at 37°C) or the hypoxic condition (5% O 2 and 7% CO 2 at 37°C).…”

Section: Methodsmentioning

confidence: 99%

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Hypoxia induces the dormant state in oocytes through expression of Foxo3

Shimamoto

Nishimura

Nagamatsu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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In mammals, most immature oocytes remain dormant in the primordial follicles to ensure the longevity of female reproductive life. A precise understanding of mechanisms underlying the dormancy is important for reproductive biology and medicine. In this study, by comparing mouse oogenesis in vivo and in vitro, the latter of which bypasses the primordial follicle stage, we defined the gene-expression profile representing the dormant state of oocytes. Overexpression of constitutively active FOXO3 partially reproduced the dormant state in vitro. Based on further geneexpression analysis, we found that a hypoxic condition efficiently induced the dormant state in vitro. The effect of hypoxia was severely diminished by disruption of the Foxo3 gene and inhibition of hypoxia-inducible factors. Our findings provide insights into the importance of environmental conditions and their effectors for establishing the dormant state. oocytes | hypoxia | Foxo3

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Section: Methodsmentioning

confidence: 99%

“…Recently, we developed a culture method in which functional oocytes can be induced from pluripotent stem cells (6,7). In the in vitro differentiation (IVDi) culture system, pluripotent stem cells bearing Blimp1-mVenus (BV) and Stella-ECFP (SC) reporter transgenes (8) were first differentiated into PGC-like cells (PGCLCs).…”

mentioning

confidence: 99%

Hypoxia induces the dormant state in oocytes through expression of Foxo3

Shimamoto

Nishimura

Nagamatsu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Converting ES/iPS cells into PGCLCs involves extensive epigenetic changes [ 83 ] which may be difficult to attain in vitro. Hayashi et al [ 84 ] published their protocols to produce functional primordial germ cells in vitro, which further differentiate into oocytes and healthy pups.…”

Section: Making Oocytes In a Dishmentioning

confidence: 99%

Making gametes from alternate sources of stem cells: past, present and future

Bhartiya

Anand

Patel

et al. 2017

Reprod Biol Endocrinol

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Infertile couples including cancer survivors stand to benefit from gametes differentiated from embryonic or induced pluripotent stem (ES/iPS) cells. It remains challenging to convert human ES/iPS cells into primordial germ-like cells (PGCLCs) en route to obtaining gametes. Considerable success was achieved in 2016 to obtain fertile offspring starting with mouse ES/iPS cells, however the specification of human ES/iPS cells into PGCLCs in vitro is still not achieved. Human ES cells will not yield patient-specific gametes unless and until hES cells are derived by somatic cell nuclear transfer (therapeutic cloning) whereas iPS cells retain the residual epigenetic memory of the somatic cells from which they are derived and also harbor genomic and mitochondrial DNA mutations. Thus, they may not be ideal starting material to produce autologus gametes, especially for aged couples. Pluripotent, very small embryonic-like stem cells (VSELs) have been reported in adult tissues including gonads, are relatively quiescent in nature, survive oncotherapy and can be detected in aged, non-functional gonads. Being developmentally equivalent to PGCs (natural precursors to gametes), VSELs spontaneously differentiate into gametes in vitro. It is also being understood that gonadal stem cells niche is compromised by oncotherapy and with age. Improving the gonadal somatic niche could regenerate non-functional gonads from endogenous VSELs to restore fertility. Niche cells (Sertoli/mesenchymal cells) can be directly transplanted and restore gonadal function by providing paracrine support to endogenous VSELs. This strategy has been successful in several mice studies already and resulted in live birth in a woman with pre-mature ovarian failure.

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“…In the current work, we show that this stem cell-derived ovarian cortex also supports increased generation of differentiating stem cells that express oocyte markers, presumably a larger cohort of primitive oogonia. While the feasibility of generating stem cell derived oocytes using reconstituted ovarian tissue has been described 18 , our work for the first time shows that oocyte development and the supporting ovarian cortical matrix can both be promoted directly from induced pluripotent stem cells 31,32 . A key observation in these studies is the capacity for differentiated, sorted mGriPSCs to contribute to the de novo generation of oocytes, as well as form ovarian follicles as evidenced by the GFP labelled follicular granulosa cells.…”

Section: Discussionmentioning

confidence: 80%

iPSC-Derived Ovarian Tissue Restores Ovarian Function in Subfertile Mice and After Gonadotoxic Chemotherapy

Elias

et al. 2019

Preprint

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Running Title: iPSC-based restoration of ovarian function following gonadotoxic chemotherapy iPSC -based restoration of ovarian function following gonadotoxic chemotherapy 2 Abstract Many oncologic therapies given to young women are gonadotoxic and associated with diminished ovarian reserve, increased risk of permanent sterility, and premature menopause. Previously, we reported the derivation of steroidogenic ovarian cells from induced pluripotent and embryonic stem cells. Derived cells not only produced reproductive hormones, but also displayed markers of ovarian tissue and primordial gametes. Here, we describe that human follicular fluid, when added to our stem cell differentiation system, enhances the steroidogenic potential of derived cells and increases the subpopulation of cells that differentiate to express the ovarian and germ cell markers GJA1 and ZP1, respectively. More importantly, using an in vivo model of chemotherapy-induced premature ovarian insufficiency in subfertile nude mice, we demonstrate that orthotopic implantation of these derived cells restores ovarian hormonal production and produces functional stem cell-derived germ cells. Collectively, these data support the hypothesis that stem cell-derived steroidogenic ovarian tissue could be used to promote neo-gametogenesis and treat premature menopause.iPSC -based restoration of ovarian function following gonadotoxic chemotherapy

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Reconstitution of mouse oogenesis in a dish from pluripotent stem cells

Cited by 65 publications

References 26 publications

Hypoxia induces the dormant state in oocytes through expression of Foxo3

Hypoxia induces the dormant state in oocytes through expression of Foxo3

Making gametes from alternate sources of stem cells: past, present and future

iPSC-Derived Ovarian Tissue Restores Ovarian Function in Subfertile Mice and After Gonadotoxic Chemotherapy

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