Efficient Derivation of Basal Progenitor Cells from Human Pluripotent Stem Cells for Modeling Esophageal Development

Many esophageal diseases including malignancy are associated with stem/progenitor cell abnormalities involving reactivation of developmental signaling pathways. However, anatomical and structural differences between species render mouse a suboptimal organism for studying esophageal development and disease mechanism. To address this issue we established an efficient protocol to generate esophageal epithelial progenitors (EPCs) from human pluripotent stem cells (hPSCs) including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Inhibition of TGFs and BMP signaling is required for the sequential differentiation of hPSCs into EPCs which can be further purified with the cell surface markers EPCAM and Integrin s4. The hPSC-derived EPCs recapitulate the normal development of the stratified squamous epithelium in the human esophagus. More importantly, a combination of hPSC differentiation and mouse genetics allows us to elucidate the critical role for NOTCH signaling in the formation of the stratified squamous epithelium. Our studies therefore not only provide an efficient approach to generate human EPCs, but also offer a new model to study the regulatory mechanisms underlying the development of the human esophagus.