Journal
CELL REPORTS
Volume 29, Issue 13, Pages 4568-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.11.083
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Funding
- NIH/NICHD [R01 HD079546]
- NIH NCATS UCLA CTSI [UL1TR0001881]
- UCLA David Geffen School of Medicine Regenerative Medicine Theme Award
- UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Innovation Award
- University of Washington Birth Defects laboratory [5R24HD000836-53]
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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.
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