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

In Barrett's oesophagus (BO), the precursor of oesophageal adenocarcinoma, the adult stratified squamous epithelium is replaced by a simple columnar phenotype. This has been considered metaplasia, i.e. the inappropriate conversion from one adult cell type to another. Alternatively, BO could represent reversion to an embryonic-fetal state when the early foregut is initially lined by simple columnar epithelium. Exploration of this hypothesis has been hampered by inadequate molecular details of human oesophageal development. Here, we adopted single-cell transcriptomic and epigenomic approaches to discover and de-code the cell types that constitute the initial primitive columnar, transitory and subsequently stratified lower oesophageal epithelium. Each stage comprises several previously undefined epithelial subpopulations. Importantly, early foregut columnar epithelial cells share core regulatory and gene expression programmes with BO. Among these, HNF4A is identified as a prominent transcriptional regulator that forms the core of a regulatory network in early foregut columnar cells. These regulatory networks are also central to programmes known to be reactivated in BO. Collectively, these data argue that the path to BO involves reactivation of pathways that define primitive embryonic and fetal epithelial cell states.