Cripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Extracellular Matrix Signaling

Background:

• Molecular mechanisms of developmental plasticity are primarily understood through transcription factors.
• Extrinsic regulation of developmental plasticity remains largely unexplored.
• Pluripotency states (naive and primed) are critical for early embryonic development.

Purpose of the Study:

• To identify novel extracellular regulators of developmental plasticity and pluripotency.
• To elucidate the role of Cripto in maintaining naive and primed pluripotent states.
• To investigate Cripto's function in metabolic reprogramming and early cell lineage decisions.

Main Methods:

• Identification of Cripto as an early epiblast marker.
• Assessment of Cripto's role in mouse embryonic stem cell (ESC) and epiblast stem cell (EpiSC) self-renewal and pluripotency.
• Analysis of Cripto's modulation of Wnt/β-catenin and Nodal/Smad2 signaling pathways.
• Investigation of Cripto's impact on metabolic reprogramming during ESC to EpiSC transition.
• Evaluation of Cripto deficiency effects on ESC lineage restriction in vitro and in vivo.

Main Results:

• Cripto is identified as a key extracellular determinant of naive and primed pluripotency.
• Cripto sustains ESC self-renewal via Wnt/β-catenin and maintains EpiSC/human ESC pluripotency via Nodal/Smad2.
• Cripto controls metabolic reprogramming during the ESC to EpiSC transition.
• Cripto deficiency attenuates ESC lineage restriction and permits trophectoderm transdifferentiation.

Conclusions:

• Cripto plays a crucial role in regulating mammalian pluripotency and early cell fate decisions.
• The findings reveal novel insights into the extrinsic regulation of pluripotency and developmental plasticity.
• Cripto exhibits earlier functions than previously recognized in embryonic development.