Defining the transcriptional signature of esophageal-to-skin lineage conversion

The ability of epithelial cells to rewire their cell fate program beyond their physiological repertoire has become a new paradigm in stem cell biology. This plasticity leaves behind the concept of strict stem cell hierarchies, opening up new exciting questions about its limits and underlying regulation. Here we developed a heterotypic 3D culture system to study the mechanisms modulating changes in the identity of adult esophageal epithelial cells. We demonstrate that, when exposed to the foreign stroma of adult skin, esophageal cells transition towards hair follicle identity and architecture. Heterotypic transplantation experiments recapitulated this cell fate conversion process in vivo. Single-cell RNA sequencing and histological analysis, capturing the temporality of this process, reveal that most esophageal cells switching towards skin identity remain in an intermediate state marked by a transient regenerative profile and a particularly strong hypoxic signature. Inhibition of HIF1a establishes the central role of this pathway in regulating epithelial cell plasticity, driving cells away from their transition state in favor of cell fate conversion.