Using human iPS cell-derived enterocytes as novel in vitro model for the evaluation of human intestinal mucosal damage
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Objective and design
The primary component in gut mucus is mucin 2 (MUC2) secreted by goblet cells. Fluctuations in MUC2 expression are considered a useful indicator for evaluating mucosal damage and protective effect of various agents using animal studies. However, there are few in vitro studies evaluating mucosal damage using MUC2 as the indicator. Hence, we attempted to establish a novel in vitro model with MUC2 as the indicator for evaluating drug-induced mucosal damage and protective effect using enterocytes derived from human iPS cells.
Compounds were added into enterocytes derived from human iPS cells, and MUC2 mRNA and protein expression levels were evaluated. Further, the effect of compounds on membrane permeability was investigated.
Nonsteroidal anti-inflammatory drugs were found to decrease MUC2 mRNA expression in enterocytes, whereas mucosal protective agents increased mRNA levels. Changes in MUC2 protein expression were consistent with those of mRNA. Additionally, our results indicated that indomethacin caused mucosal damage, affecting membrane permeability of the drug. Moreover, we observed protective effect of rebamipide against the indomethacin-induced permeability increase.
The developed model could facilitate evaluating drug-induced mucosal damage and protective effects of various agents and could impact drug development studies regarding pharmacological efficacy and safety.
KeywordsHuman iPS cells Enterocytes Mucin 2 Nonsteroidal anti-inflammatory drugs Mucosal protective agents
The authors are extremely grateful to Dr. Hidenori Akutsu, Dr. Yoshitaka Miyagawa, Dr. Hajime Okita, Dr. Nobutaka Kiyokawa, Dr. Masashi Toyoda, and Dr. Akihiro Umezawa for providing the human iPS cells.
SK, MS, TH, TI, and TM participated in research design; SK and MS conducted experiments and performed data analysis; SK, MS, TH, TI, and TM wrote or contributed to the writing of the manuscript.
This work was supported by Grant-in-Aid for Research in Nagoya City University in 2017, and Agency for Medical Research and Development (AMED) under Grant Number 17be0304203h0001.
Compliance with ethical standards
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
- 35.Murakami K, Okajima K, Harada N, Isobe H, Okabe H. Rebamipide prevents indomethacin-induced gastric mucosal lesion formation by inhibiting activation of neutrophils in rats. Dig Dis Sci. 1998;43:139–42.Google Scholar
- 40.Yamao J, Kikuchi E, Matsumoto M, Nakayama M, Ann T, et al. Assessing the efficacy of famotidine and rebamipide in the treatment of gastric mucosal lesions in patients receiving long-term NSAID therapy (FORCE—famotidine or rebamipide in comparison by endoscopy). J Gastroenterol. 2006;41:1178–85.CrossRefGoogle Scholar