TY - JOUR
T1 - A Novel Organoid Model of Damage and Repair Identifies HNF4α as a Critical Regulator of Intestinal Epithelial Regeneration
AU - Montenegro-Miranda, Paula S.
AU - van der Meer, Jonathan H. M.
AU - Jones, Christine
AU - Meisner, Sander
AU - Vermeulen, Jacqueline L. M.
AU - Koster, Jan
AU - Wildenberg, Manon E.
AU - Heijmans, Jarom
AU - Boudreau, Francois
AU - Ribeiro, Agnes
AU - van den Brink, Gijs R.
AU - Muncan, Vanesa
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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 γ-radiation on small-intestinal organoids. We then used this model to identify novel regulators of intestinal regeneration. Results: We identified hepatocyte nuclear factor 4α (HNF4α) 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 HNF4α as a crucial regulator of intestinal regeneration. Transcript profiling: GSE141515 and GSE141518.
AB - 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 γ-radiation on small-intestinal organoids. We then used this model to identify novel regulators of intestinal regeneration. Results: We identified hepatocyte nuclear factor 4α (HNF4α) 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 HNF4α as a crucial regulator of intestinal regeneration. Transcript profiling: GSE141515 and GSE141518.
KW - Irradiation
KW - Organoids
KW - Regeneration
UR - http://www.scopus.com/inward/record.url?scp=85086435355&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jcmgh.2020.02.007
DO - https://doi.org/10.1016/j.jcmgh.2020.02.007
M3 - Article
C2 - 32145468
SN - 2352-345X
VL - 10
SP - 209
EP - 223
JO - Cellular and Molecular Gastroenterology and Hepatology
JF - Cellular and Molecular Gastroenterology and Hepatology
IS - 2
ER -