A Novel Organoid Model of Damage and Repair Identifies HNF4? as a Critical Regulator of Intestinal Epithelial Regeneration.

ABSTRACT: BACKGROUND & AIMS:Recent evidence has suggested that the intact intestinal epithelial barrier protects our body from a range of immune-mediated diseases. The epithelial layer has an impressive ability to reconstitute and repair upon damage and this process of repair increasingly is seen as a therapeutic target. In vitro models to study this process in primary intestinal cells are lacking. METHODS:We established and characterized an in vitro model of intestinal damage and repair by applying ?-radiation on small-intestinal organoids. We then used this model to identify novel regulators of intestinal regeneration. RESULTS:We identified hepatocyte nuclear factor 4? (HNF4?) as a pivotal upstream regulator of the intestinal regenerative response. Organoids lacking Hnf4a were not able to propagate in vitro. Importantly, intestinal Hnf4a knock-out mice showed impaired regeneration after whole-body irradiation, confirming intestinal organoids as a valuable alternative to in vivo studies. CONCLUSIONS:In conclusion, we established and validated an in vitro damage-repair model and identified HNF4? as a crucial regulator of intestinal regeneration. Transcript profiling: GSE141515 and GSE141518.

SUBMITTER: Montenegro-Miranda PS 

PROVIDER: S-EPMC7301200 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature