In vitro models of the human esophagus reveal ancestrally diverse response to injury

Ferrer-Torres, Daysha; Wu, Joshua H.; Zhang, Charles J.; Hammer, Max A.; Dame, Michael; Wu, Angeline; Holloway, Emily M.; Karpoff, Kateryna; McCarthy, Caroline L.; Bohm, Margaret S; Huang, Sha; Tsai, Yu-Hwai; Hogan, Simon P.; Turgeon, Danielle Kim; Lin, Jules; Higgins, Peter D.R.; Sexton, Jonathan; Spence, Jason R.

European Americans (EA) are more susceptible to esophageal tissue damage and inflammation when exposed to gastric acid and bile acid reflux and have a higher incidence of esophageal adenocarcinoma when compared to African Americans (AA). Population studies have implicated specific genes for these differences; however, the underlying cause for these differences is not well understood. We describe a robust long-term culture system to grow primary human esophagus in vitro, use single cell RNA sequencing to compare primary human biopsies to their in vitro counterparts, identify known and new molecular markers of basal cell types, and demonstrate that in vivo cellular heterogeneity is maintained in vitro. We further developed an ancestrally diverse biobank and a high-content, image based, screening assay to interrogate bile-acid injury response. These results demonstrated that AA esophageal cells responded significantly differently than EA-derived cells, mirroring clinical findings, having important implications for addressing disparities in early drug development pipelines.