BMP4 drives primed to naïve transition through PGC-like state

Area of Science:

• Stem cell biology
• Developmental biology
• Epigenetics

Background:

• Pluripotency exists in multiple states in mouse and human stem cells.
• Understanding cell fate transitions is crucial for developmental biology.

Purpose of the Study:

• To investigate the transition from primed to naïve pluripotency in mouse stem cells.
• To elucidate the intermediate cell states involved in this transition.
• To gain insights into germ cell development.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of a BMP4-induced mouse primed to naïve transition (BiPNT) system.
• In vivo assays for spermatogenesis.
• DOT1L inhibition and analysis of epigenetic modifications (H3K79me2).
• Gene knockout studies (Prdm1/Blimp1, Gata2).

Main Results:

• Epiblast stem cells bifurcate into naïve (c-Kit+) and trophoblast-like (c-Kit-) cells.
• The naïve branch transitions through a primordial germ cell-like cells (PGCLCs) intermediate.
• PGCLCs are capable of spermatogenesis in vivo.
• DOT1L inhibition facilitates primed to PGCLC transition by reducing H3K79me2 on Gata3/6.
• Prdm1/Blimp1 is essential for PGCLCs and naïve cells.
• Gata2 promotes trophoblast-like fate and inhibits the PGC-like state.

Conclusions:

• Primed to naïve pluripotency transition involves a PGCLC intermediate, not a direct reversal.
• This pathway provides an alternative route for cell fate reprogramming.
• The study enhances understanding of germ cell development mechanisms.