In vitro reconstitution of epigenetic reprogramming in the human germ line

Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia. This process ensures sexually dimorphic germ cell development for totipotency 1 . In vitro reconstitution of epigenetic reprogramming in humans rema...

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Veröffentlicht in:Nature (London) 2024-07, Vol.631 (8019), p.170-178
Hauptverfasser: Murase, Yusuke, Yokogawa, Ryuta, Yabuta, Yukihiro, Nagano, Masahiro, Katou, Yoshitaka, Mizuyama, Manami, Kitamura, Ayaka, Puangsricharoen, Pimpitcha, Yamashiro, Chika, Hu, Bo, Mizuta, Ken, Tsujimura, Taro, Yamamoto, Takuya, Ogata, Kosuke, Ishihama, Yasushi, Saitou, Mitinori
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Sprache:eng
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Zusammenfassung:Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia. This process ensures sexually dimorphic germ cell development for totipotency 1 . In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here we establish a strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem-cell-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (about >10 10 -fold). Bone morphogenetic protein (BMP) signalling is a key driver of these processes. BMP-driven hPGCLC differentiation involves attenuation of the MAPK (ERK) pathway and both de novo and maintenance DNA methyltransferase activities, which probably promote replication-coupled, passive DNA demethylation. hPGCLCs deficient in TET1, an active DNA demethylase abundant in human germ cells 2 , 3 , differentiate into extraembryonic cells, including amnion, with de-repression of key genes that bear bivalent promoters. These cells fail to fully activate genes vital for spermatogenesis and oogenesis, and their promoters remain methylated. Our study provides a framework for epigenetic reprogramming in humans and an important advance in human biology. Through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, our results also represent a milestone for human in vitro gametogenesis research and its potential translation into reproductive medicine. A new strategy that involves signalling-molecule-driven differentiation can induce epigenetic reprogramming of human pluripotent stem cell-derived primordial germ cell-like cells to pro-spermatogonia and oogonia-like cells with massive propagation and high efficiency.
ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-024-07526-6