Heritable imprinting defect caused by epigenetic abnormalities in mouse spermatogonial stem cells

Area of Science:

• Developmental biology
• Epigenetics
• Stem cell biology

Background:

• Male germ cells undergo epigenetic reprogramming during fetal development to establish spermatogonial stem cells (SSCs).
• The developmental potential and maturation process of fetal germ cells into SSCs remain poorly understood.
• Understanding these processes is crucial for regenerative medicine and reproductive biology.

Purpose of the Study:

• To develop a culture system for long-term proliferation of fetal germ cells.
• To investigate the developmental potential and epigenetic stability of cultured fetal germ cells.
• To assess the impact of in vitro culture on the ability of fetal germ cells to undergo epigenetic reprogramming.

Main Methods:

• Culture of male germ cells from mouse embryos (12.5-18.5 days postcoitum).
• Expansion of germ cells using glial cell line-derived neurotrophic factor (GDNF).
• Assessment of teratoma formation, seminiferous tubule repopulation, spermatogenesis, and genomic imprinting in offspring.

Main Results:

• Cultured fetal germ cells proliferated long-term and exhibited spermatogonia potential, repopulating seminiferous tubules and producing sperm.
• Offspring derived from cultured cells displayed growth abnormalities and defects in genomic imprinting.
• The observed imprinting defects were heritable for at least four generations and accompanied by abnormal histone modifications and DNA methylation patterns.

Conclusions:

• Fetal germ cells possess a limited capacity for pluripotent cell conversion after in vitro culture.
• Long-term in vitro culture impairs the epigenetic reprogramming ability of fetal germ cells.
• These findings highlight the critical role of in vivo epigenetic regulation during germ cell development and maturation.