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

Abstract

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.