Human Primordial Germ Cells Are Specified from Lineage-Primed Progenitors

Di Chen, Na Sun, Lei Hou, Rachel Kim, Jared Faith, Marianna Aslanyan, Yu Tao, Yi Zheng, Jianping Fu, Wanlu Liu, Manolis Kellis, Amander Clark

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

In vitro gametogenesis is the process of making germline cells from human pluripotent stem cells. The foundation of this model is the quality of the first progenitors called primordial germ cells (PGCs), which in vivo are specified during the peri-implantation window of human development. Here, we show that human PGC (hPGC) specification begins at day 12 post-fertilization. Using single-cell RNA sequencing of hPGC-like cells (hPGCLCs) differentiated from pluripotent stem cells, we discovered that hPGCLC specification involves resetting pluripotency toward a transitional state with shared characteristics between naive and primed pluripotency, followed by differentiation into lineage-primed TFAP2A+ progenitors. Applying the germline trajectory to TFAP2C mutants reveals that TFAP2C functions in the TFAP2A+ progenitors upstream of PRDM1 to regulate the expression of SOX17. This serves to protect hPGCLCs from crossing the Weismann's barrier to adopt somatic cell fates and, therefore, is an essential mechanism for successfully initiating in vitro gametogenesis.

Original languageEnglish (US)
Pages (from-to)4568-4582.e5
JournalCell Reports
Volume29
Issue number13
DOIs
StatePublished - Dec 24 2019
Externally publishedYes

Keywords

  • TFAP2A
  • TFAP2C
  • germ cells
  • pluripotency
  • single cell RNA-sequencing
  • stem cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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