Human primordial germ cell commitment in vitro associates with a unique PRDM14 expression profile.
Primordial germ cells (PGCs) develop only into sperm and oocytes in vivo. The molecular mechanisms underlying human PGC specification are poorly understood due to inaccessibility of cell materials and lack of in vitro models for tracking the earliest stages of germ cell development. Here, we describe a defined and stepwise differentiation system for inducing pre-migratory PGC-like cells (PGCLCs) from human pluripotent stem cells (PSCs). In response to cytokines, PSCs differentiate first into a heterogeneous mesoderm-like cell population and then into PGCLCs, which exhibit minimal PRDM14 expression. PGC specification in humans is similar to the murine process, with the sequential activation of mesodermal and PGC genes, and the suppression of neural induction and of de novo DNA methylation, suggesting that human PGC formation is induced via epigenesis, the process of germ cell specification via inductive signals from surrounding somatic cells. This study demonstrates that PGC commitment in humans shares key features with that of the mouse, but also highlights key differences, including transcriptional regulation during the early stage of human PGC development (3-6 weeks). A more comprehensive understanding of human germ cell development may lead to methodology for successfully generating PSC-derived gametes for reproductive medicine.
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Fumihiro
F
Sugawa
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany Group of Computational Biology and Bioinformatics, Biodonostia Health Research Institute, San Sebastián, Spain IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
Marcos J
MJ
Araúzo-Bravo
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Juyong
J
Yoon
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Kee-Pyo
KP
Kim
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Shinya
S
Aramaki
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Guangming
G
Wu
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Martin
M
Stehling
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Olympia E
OE
Psathaki
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
Karin
K
Hübner
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany Medical Faculty, University of Münster, Münster, Germany office@mpi-muenster.mpg.de.
Hans R
HR
Schöler
D028341:Activins / Q000494:pharmacology; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005854:Germ Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology*; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors; D059467:Transcriptome / Q000187:drug effects
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D004268:DNA-Binding Proteins; C524724:PRDM14 protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C422405:activin A; D016222:Fibroblast Growth Factor 2; D028341:Activins
BLIMP1; human pluripotent stem cells; primordial germ cell precursors; primordial germ cell specification