Science. 2018 Sep 20. pii: eaat1674. doi: 10.1126/science.aat1674. [Epub ahead of print]

Generation of human oogonia from induced pluripotent stem cells in vitro.

Yamashiro C^1,2, Sasaki K^1,2, Yabuta Y^1,2, Kojima Y^1,2,3,4, Nakamura T^1,2, Okamoto I^1,2, Yokobayashi S^1,2,4, Murase Y^1,2, Ishikura Y^1,2, Shirane K^5,6, Sasaki H^5,6, Yamamoto T^3,4,7, Saitou M^8,2,3,4.

Abstract

Human in vitro gametogenesis may transform reproductive medicine. Human pluripotent stem cells (hPSCs) have been induced into primordial germ cell-like cells (hPGCLCs); however, further differentiation to a mature germ cell has not been achieved. Here, we show that hPGCLCs differentiate progressively into oogonia-like cells during a long-term in vitro culture (~four months) in xenogeneic reconstituted ovaries with mouse embryonic ovarian somatic cells. The hPGCLC-derived oogonia display hallmarks of epigenetic reprogramming, i.e., genome-wide DNA demethylation, imprint erasure, and extinguishment of aberrant DNA methylation in hPSCs, and acquire an immediate precursory state for meiotic recombination. Furthermore, the inactive X chromosome shows a progressive demethylation and reactivation, albeit partially. These findings establish the germline competence of hPSCs and provide a critical step toward human in vitro gametogenesis.