Metabolic switch and epithelial-mesenchymal transition cooperate to regulate pluripotency

Area of Science:

• Cell Biology
• Developmental Biology
• Epigenetics

Background:

• Oxidative phosphorylation to glycolysis switch (OGS) and epithelial-mesenchymal transition (EMT) are crucial for cellular reprogramming.
• The interplay between OGS and EMT in early reprogramming remains largely uncharacterized.

Purpose of the Study:

• To investigate the connection between OGS and EMT during mouse reprogramming.
• To elucidate the mechanisms by which OGS and EMT cooperate to regulate pluripotency induction.
• To define the novel pluripotent cell state induced by the combined OGS and EMT events.

Main Methods:

• Induction of early EMT using a chemically defined medium during mouse reprogramming.
• Analysis of metabolic changes, specifically OGS.
• Investigation of transcriptional activation and epigenetic factor regulation (Bmi1, Ctcf, Ezh2, Kdm2b, Wdr5).
• Characterization of the resulting pluripotent stem cell state.

Main Results:

• Early EMT induction facilitated OGS, forming a positive feedback loop.
• This cooperation accelerated early pluripotency induction by upregulating epigenetic factors.
• At later stages, sustained OGS and inhibited mesenchymal-epithelial transition trapped cells in a unique intermediate pluripotent state, hindering further reprogramming to the naive state.
• The identified pluripotent state resembles epiblasts from early mouse embryos (E4.5-E5.5).

Conclusions:

• The time-dependent cooperation between OGS and EMT is critical for regulating pluripotency.
• This interaction influences the trajectory of cellular reprogramming, leading to distinct intermediate pluripotent states.
• Findings expand the understanding of pluripotency regulation and early embryonic development.