Embryonic stem cell self-renewal pathways converge on the transcription factor Tfcp2l1

Area of Science:

• Stem cell biology
• Epigenetics
• Transcription factors

Background:

• Mouse embryonic stem cell (mESC) self-renewal is maintained by leukaemia inhibitory factor (LIF)/signal transducer and activator of transcription 3 (Stat3) signaling or dual inhibition (2i) of glycogen synthase kinase 3 (Gsk3) and mitogen-activated protein kinase kinase (MEK).
• Previous studies identified downstream targets of these pathways that partially support self-renewal upon overexpression, but no common targets were found.

Purpose of the Study:

• To identify common targets shared between LIF/Stat3 and 2i self-renewal pathways in mESCs.
• To investigate the role of Tfcp2l1 in maintaining pluripotency and self-renewal.
• To explore the potential of Tfcp2l1 in reprogramming epiblast stem cells.

Main Methods:

• Overexpression of Tfcp2l1 in mESCs.
• Assessment of self-renewal capacity.
• Analysis of Nanog expression levels.
• Reprogramming of post-implantation epiblast stem cells.

Main Results:

• Tfcp2l1 was identified as a common downstream target of both LIF/Stat3 and 2i pathways.
• Forced expression of Tfcp2l1 mimicked the self-renewal-promoting effects of LIF and 2i.
• Tfcp2l1 upregulated Nanog expression and promoted self-renewal in a Nanog-dependent manner.
• Tfcp2l1 successfully reprogrammed post-implantation epiblast stem cells to a naïve pluripotent state.

Conclusions:

• Tfcp2l1 acts as a crucial mediator at the intersection of LIF/Stat3 and 2i self-renewal pathways.
• Tfcp2l1 plays a critical role in maintaining ESC identity and ground-state pluripotency.
• Tfcp2l1 represents a key factor for understanding and manipulating ESC self-renewal.