Abstract
Human germ cells are the foundation of human reproduction and development, ensuring heredity and contributing to genetic diversity. Accordingly, their anomalies lead to critical diseases, including infertility. Recent advances in genomics and stem cell-based in vitro gametogenesis research have expanded our knowledge of how human germ cells are specified and differentiate during embryonic and fetal development, elucidating evolutionarily distinctive as well as conserved properties of human germ cell development. Here, based on the evidence from both in vivo and in vitro studies, we provide an integrated review of the progress in our understanding of human embryonic and fetal germ cell development, encompassing germ cell specification, epigenetic reprogramming and sex-specific germ cell development. Knowledge of the mechanisms of human germ cell development will enable its in vitro reconstitution, which in turn will serve as a foundation for innovative medical strategies to prevent germ cell-related diseases, including infertility.
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Acknowledgements
The authors thank the members of their laboratory for their helpful input into this study, and M. Yoshida and M. Kawasaki for their assistance. This work was supported by Grants-in-Aid for Specially Promoted Research from JSPS (22H04920) and grants from the Open Philanthropy Project (GV673604305) to M.S.
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M.S., K.M. and M.N. discussed the article content, wrote, edited and reviewed the manuscript before submission. M.S. supervised the work.
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M.S. and K.M., together with Kyoto University, have filed provisional patent applications for germ cell culture and the induction of germ cells from hPSCs. M.N. declares no competing interests.
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Glossary
- 14-day rule
-
An internationally adopted ethical principle that prohibits in vitro culture of human embryos beyond 14 days post-fertilization or until formation of the primitive streak. It is now under reconsideration following the 2021 revision of the guidelines by the International Society for Stem Cell Research (ISSCR), which permits limited extensions under strict oversight.
- DNA translesion synthesis
-
A DNA damage tolerance pathway that allows DNA replication to proceed across sites of damage. It is carried out by specialized DNA polymerases with active sites that can accommodate distorted or damaged DNA templates, enabling the bypass of lesions that would otherwise stall replication forks.
- Fanconi anaemia pathway
-
A specialized DNA repair mechanism that resolves interstrand crosslinks. At least 22 Fanconi anaemia proteins (FANCA–FANCT), along with associated factors, cooperate to repair DNA damage, particularly during DNA replication.
- Genomic imprinting
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An epigenetic mechanism that drives mono-allelic gene expression based on parental origin, regulated by DNA methylation established during gametogenesis and maintained throughout development.
- Imprinting control regions
-
Genomic loci that carry parent-of-origin-specific epigenetic marks and regulate gene expression in an allele-specific manner, serving as the basis for genomic imprinting.
- Ovarian reserve
-
The finite pool of non-growing (that is, primarily primordial) follicles established during fetal development, which determines female fertility potential throughout reproductive life.
- Xenogeneic
-
Describes any interaction or procedure involving the use of biological materials derived from different species. Here, it describes the aggregation of human primordial germ cell-like cell-derived cells with mouse gonadal somatic cells.
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Saitou, M., Nagano, M. & Mizuta, K. Mechanisms of human germ cell development. Nat Rev Mol Cell Biol (2025). https://doi.org/10.1038/s41580-025-00893-6
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DOI: https://doi.org/10.1038/s41580-025-00893-6
