Esophagus extracellular matrix with microenvironmental complexity for esophageal organoids

Esophageal organoids have the potential to serve as promising therapeutics for esophageal mucosal damage, but their application remains largely unexplored. A critical initial step in this application involves addressing the challenges posed by Matrigel (MAT)-based conventional organoid culture, as its tumor-derived origin hinders clinical applications. In this study, we demonstrate the application of decellularized esophagus-derived extracellular matrix (EEM) to the culture and transplantation of esophageal organoids, inspired by excellent biocompatibility and esophageal mimicry of EEM. Our comprehensive proteomic analysis reveals that EEM recapitulates microenvironmental complexity suitable for esophageal organoids by providing diverse esophagus-specific proteins absent in MAT. Esophageal organoids grown in EEM hydrogel can expand through multiple passages and exhibit comparable or elevated expression of esophagus-related genes compared to those grown in MAT. The transplantation of esophageal organoids with EEM not only promotes epithelial regeneration but also mitigates fibrosis at the wound site in a mouse model of an esophageal ulcer. Furthermore, the protein profiles of esophageal tissues undergoing regeneration support the activation of wound healing following organoid transplantation. Taken together, the EEM-based approach for esophageal organoid culture and transplantation would pave the way for advancing esophageal organoid applications by providing a stable and refined matrix to replace MAT.