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Gut Epithelial Inositol Polyphosphate Multikinase Alleviates Experimental Colitis via Governing Tuft Cell Homeostasis

Authors
 Seung Eun Park  ;  Dongeun Lee  ;  Jae Woong Jeong  ;  Su-Hyung Lee  ;  Seung Ju Park  ;  Jaeseung Ryu  ;  Se Kyu Oh  ;  Hanseul Yang  ;  Sungsoon Fang  ;  Seyun Kim 
Citation
 CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, Vol.14(6) : 1235-1256, 2022-09 
Journal Title
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Issue Date
2022-09
MeSH
Animals ; Colitis* / chemically induced ; Colitis* / drug therapy ; Dextran Sulfate ; Homeostasis ; Mice ; Phosphotransferases (Alcohol Group Acceptor) / genetics
Keywords
Colitis ; Colon ; Epithelial Barrier ; IBD ; IPMK ; Single-Cell RNA-Seq ; Tuft Cell
Abstract
Background & aims: Inositol polyphosphate multikinase (IPMK), an essential enzyme for inositol phosphate metabolism, has been known to mediate major biological events such as growth. Recent studies have identified single-nucleotide polymorphisms in the IPMK gene associated with inflammatory bowel disease predisposition. Therefore, we aimed to investigate the functional significance of IPMK in gut epithelium.

Methods: We generated intestinal epithelial cell (IEC)-specific Ipmk knockout (IPMKΔIEC) mice, and assessed their vulnerability against dextran sulfate sodium-induced experimental colitis. Both bulk and single-cell RNA sequencing were performed to analyze IPMK-deficient colonic epithelial cells and colonic tuft cells.

Results: Although IPMKΔIEC mice developed normally and showed no intestinal abnormalities during homeostasis, Ipmk deletion aggravated dextran sulfate sodium-induced colitis, with higher clinical colitis scores, and increased epithelial barrier permeability. Surprisingly, Ipmk deletion led to a significant decrease in the number of tuft cells without influencing other IECs. Single-cell RNA sequencing of mouse colonic tuft cells showed 3 distinct populations of tuft cells, and further showed that a transcriptionally inactive population was expanded markedly in IPMKΔIEC mice, while neuronal-related cells were relatively decreased.

Conclusions: Cholinergic output from tuft cells is known to be critical for the restoration of intestinal architecture upon damage, supporting that tuft cell-defective IPMKΔIEC mice are more prone to colitis. Thus, intestinal epithelial IPMK is a critical regulator of colonic integrity and tissue regeneration by determining tuft cell homeostasis and affecting cholinergic output.
Files in This Item:
T202205115.pdf Download
DOI
10.1016/j.jcmgh.2022.08.004
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Fang, Sungsoon(황성순) ORCID logo https://orcid.org/0000-0003-0201-5567
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/191922
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