Metaplastic Barrett's oesophagus represents reversion to a developmental-like epithelial cell state.

Area of Science:

• Gastroenterology
• Developmental Biology
• Molecular Biology

Background:

• Barrett's oesophagus (BO) is a precursor to oesophageal adenocarcinoma.
• BO involves the replacement of stratified squamous epithelium with simple columnar epithelium.
• The cellular origin of BO is debated: metaplasia versus reversion to an embryonic state.

Purpose of the Study:

• To investigate the molecular and cellular basis of human oesophageal development.
• To determine if BO represents a reversion to an embryonic cell state.
• To identify molecular regulators involved in oesophageal development and BO.

Main Methods:

• Single-cell transcriptomic analysis
• Epigenomic profiling
• Comparative analysis of developmental and disease states

Main Results:

• Identified previously undefined epithelial subpopulations during oesophageal development.
• Demonstrated that early foregut columnar epithelial cells share core gene expression programs with BO.
• Identified HNF4A as a key transcriptional regulator in early foregut cells and its reactivation in BO.

Conclusions:

• The development of Barrett's oesophagus may involve the reactivation of primitive embryonic and fetal epithelial cell pathways.
• HNF4A plays a central role in the regulatory networks governing both early oesophageal development and BO.
• Findings challenge the traditional metaplasia view, suggesting a developmental reversion mechanism for BO.