Depletion of Sorcs3 Activates Totipotency in Mouse Embryonic Stem Cells by Modulating Key Signaling Pathways.

Area of Science:

• Stem cell biology
• Developmental biology
• Genetics

Background:

• Totipotency, the ability to form a complete organism and extraembryonic tissues, is transient in early development.
• Establishing sustainable totipotent stem cells is a significant challenge in regenerative medicine.

Purpose of the Study:

• To investigate the role of Sorcs3 in murine embryonic stem cells (ESCs).
• To explore the potential of Sorcs3-depleted ESCs in achieving a totipotent-like state.
• To establish a model for studying early embryonic development and totipotency.

Main Methods:

• Sorcs3 knockout (SKO) in murine ESCs.
• Analysis of differentiation into embryonic and extraembryonic lineages.
• Formation of blastocyst-like structures.
• Gene expression analysis (Tfap2c).
• Single-cell transcriptome analysis.
• Pathway inhibition studies (TGF-β, PI3K-AKT, lysosome).

Main Results:

• Sorcs3 depletion in ESCs induced a totipotent-like state, enabling differentiation into both embryonic and extraembryonic lineages.
• SKO-ESCs self-assembled into blastocyst-like structures, serving as a model for early development.
• Totipotency in SKO-ESCs was linked to Tfap2c gene activation; its deletion impaired developmental potential.
• Inhibition of TGF-β, PI3K-AKT, and lysosome pathways activated totipotency in ESCs.

Conclusions:

• Sorcs3 depletion is a viable strategy for generating totipotent-like ESCs.
• Tfap2c is a critical regulator of totipotency in this model.
• Targeting specific signaling pathways can induce totipotency in ESCs.
• This research provides a platform for studying totipotency and establishing stem cells in defined media.