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Reconstitution of sex-determination process and testicular environment using mouse pluripotent stem cells

ABSTRACT: Proper differentiation of gonadal somatic cells is crucial for sex determination and subsequent production of sex hormone and gametes. A proper reconstitution of the process in culture will provide not only an appropriate tool for fully understanding the process but also creation of gametes in culture, so called in vitro gametogenesis. Here, we report reconstitution of testicular gonadal somatic cells using mouse pluripotent stem cells. The reconstitution recapitulated a trajectory of the sex-determination process in vivo and consequently provide cell types forming seminiferous tubules and adjacent interstitial tissues including steroidogenic cells. Importantly, the reconstituted testicular tissue incorporated pluripotent stem cell-derived primordial germ cells and provided an environment sufficient for differentiation of spermatogonial stem cells. These spermatogonial stem cells can propagated in culture while keeping potential to differentiate into spermatozoa capable of full-term development with in vitro fertilization followed by transplantation into surrogate mothers. With this reconstitution system, embryonic tissues are no longer required to obtain male germ stem cells, encouraging application to other mammalian species. This study contributes to deeper understanding sex determination process and to creating an alternative source of male germ line in culture.

ORGANISM(S): Mus

PROVIDER: GSE299512 | GEO | 2026/06/05

REPOSITORIES: GEO

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Project description:Spermatogonial stem cells undergo both self-renewal to maintain the stem cell population and differentiation to produce mature sperm. These processes are controlled by both stem cell-intrinsic and external niche factors. DOT1L, the sole H3K79 methyltransferase, is dispensable for mouse embryonic stem cell self-renewal but instead functions as a barrier to somatic cell reprogramming. Here we show that DOT1L is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L in the germ cells show a failure in the maintenance of spermatogonial stem cells without a block in spermatogenic cell differentiation and thus a progressive loss of germ cells, leading to a Sertoli-cell-only syndrome. Chemical inhibition of DOT1L in cultured stem cells reduces the spermatogonial stem cell activity after transplantation. RNA-seq analysis reveals downregulation of Hoxc cluster genes in DOT1L-inhibited spermatogonia stem cells. Single cell RNA-seq analysis demonstrates that inhibition of DOT1L sequesters spermatogonial stem cells in a primitive state and prevents them from transitioning to a progenitor state. These results identify a new function for DOT1L in adult stem cells and provides a paradigm for regulation of spermatogonial stem cell self-renewal. Self-renewal of spermatogonial stem cells is vital to life-long production of male gametes and thus fertility. However, the underlying mechanisms remain enigmatic. Here, we show that DOT1L, the sole H3K79 methyltransferase, is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L fail to maintain spermatogonial stem cells, characterized by a sequential loss of germ cells from spermatogonia to spermatids and ultimately a Sertoli-cell-only syndrome. Inhibition of DOT1L reduces the stem cell activity after transplantation, prevents spermatogonial stem cells from transitioning to a progenitor state, and sequesters them in a primitive state. Furthermore, DOT1L promotes expression of the fate-determining HoxC transcription factors in spermatogonial stem cells. Our findings identify an essential function for DOT1L in adult stem cells and provide an epigenetic paradigm for regulation of spermatogonial stem cells.

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Reconstitution of sex-determination process and testicular environment using mouse pluripotent stem cells

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