@article{7644acfe303d4d12b850eabceaa98a60,
title = "An in vitro chronic damage model impairs inflammatory and regenerative responses in human colonoid monolayers",
abstract = "Acute damage to the intestinal epithelium can be repaired via de-differentiation of mature intestinal epithelial cells (IECs) to a stem-like state, but there is a lack of knowledge on how intestinal stem cells function after chronic injury, such as in inflammatory bowel disease (IBD). We developed a chronic-injury model in human colonoid monolayers by repeated rounds of air-liquid interface and submerged culture. We use this model to understand how chronic intestinal damage affects the ability of IECs to (1) respond to microbial stimulation, using the Toll-like receptor 5 (TLR5) agonist FliC and (2) regenerate and protect the epithelium from further damage. Repeated rounds of damage impair the ability of IECs to regrow and respond to TLR stimulation. We also identify mRNA expression and DNA methylation changes in genes associated with IBD and colon cancer. This methodology results in a human model of recurrent IEC injury like that which occurs in IBD.",
keywords = "ER stress, air-liquid interface, chronic damage, epigenetics, flagellin, inflammatory bowel diseases, intestinal stem cells, organoids, regeneration",
author = "Rees, {William D.} and Nikita Telkar and Lin, {David T.S.} and Wong, {May Q.} and Chad Poloni and Ayda Fathi and Michael Kobor and Zachos, {Nicholas C.} and Steiner, {Theodore S.}",
note = "Funding Information: This work was funded by a Mitacs Accelerate award to W.D.R. and a Grant-In-Aid of Research from Crohn's and Colitis Canada to T.S.S. The authors wish to acknowledge the Integrated Physiology Core of the Hopkins Conte Digestive Disease Basic and Translational Research Core Center for providing human colonoids (NIH P30 DK089502). The authors wish to acknowledge BC Children's Hospital Research Institute (BCCHR) Core Technologies and Services, Vancouver, BC, Canada for immunofluorescent imaging presented in this paper. W.D.R.: project conception, experiments, manuscript preparation. N.T,: bioinformatic analysis, figures. D.L.: DNAm, data analysis, and figures. M.W. C.P. and A.F.: experiment assistance. M.K.: study design, interpretation. N.C.Z.: colonoid sourcing, study design, data interpretation, manuscript review. T.S.S.: study design, supervision, data interpretation, manuscript preparation. The authors declare no competing interests. Funding Information: This work was funded by a Mitacs Accelerate award to W.D.R. and a Grant-In-Aid of Research from Crohn's and Colitis Canada to T.S.S. The authors wish to acknowledge the Integrated Physiology Core of the Hopkins Conte Digestive Disease Basic and Translational Research Core Center for providing human colonoids (NIH P30 DK089502). The authors wish to acknowledge BC Children's Hospital Research Institute (BCCHR) Core Technologies and Services, Vancouver, BC, Canada for immunofluorescent imaging presented in this paper. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = jan,
day = "18",
doi = "10.1016/j.celrep.2021.110283",
language = "English (US)",
volume = "38",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}