STAT3 regulates basal cell identity and morphogenesis during early esophageal development

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Epithelial Biology

Background:

• The transcription factor STAT3 (Signal transducer and activator of transcription 3) has known roles in epithelial biology.
• Its specific function in human esophageal development is not well understood.

Purpose of the Study:

• To investigate the role of STAT3 in regulating human esophageal epithelial differentiation.
• To understand STAT3's function during early human esophageal lineage commitment using stem cell models.

Main Methods:

• Utilized 2D and 3D human induced pluripotent stem cell (hiPSC)-derived organoid platforms.
• Employed CRISPR-mediated knockout and siRNA to inhibit STAT3 function.
• Analyzed the expression of key esophageal progenitor cell (EPC) and differentiation markers, including TP63.

Main Results:

• STAT3 is dispensable for definitive endoderm and anterior foregut endoderm specification.
• STAT3 becomes essential for esophageal progenitor cell (EPC) specification and differentiation.
• STAT3 inhibition impairs EPC marker expression (e.g., TP63), reduces epithelial proliferation, and disrupts 3D organoid formation.
• STAT3 is highly expressed in human fetal esophageal tissue and hiPSC-derived organoids.
• STAT3 deletion in mouse esophagus did not affect epithelial architecture, indicating species-specific roles.

Conclusions:

• STAT3 is a critical regulator of basal cell identity in the developing human esophagus.
• STAT3 plays a vital role in epithelial morphogenesis during human esophageal development.
• STAT3 represents a key developmental checkpoint in early human esophageal lineage commitment.