Enteroendocrine Progenitor Cell-Enriched miR-7 Regulates Intestinal Epithelial Proliferation in an Xiap-Dependent Manner.
Animals
Cell Lineage
/ genetics
Cell Proliferation
/ genetics
Cells, Cultured
Computational Biology
Enteroendocrine Cells
/ physiology
ErbB Receptors
/ metabolism
Feeding Behavior
/ physiology
Female
Inhibitor of Apoptosis Proteins
/ genetics
Intestinal Mucosa
/ cytology
Male
Mice
Mice, Transgenic
MicroRNAs
/ metabolism
Models, Animal
Organoids
Primary Cell Culture
RNA-Seq
Signal Transduction
/ genetics
Single-Cell Analysis
Stem Cells
/ physiology
Enteroendocrine Lineage
Enteroid
Proliferation
Small Intestine
miR-7
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2020
2020
Historique:
received:
14
08
2019
revised:
29
10
2019
accepted:
07
11
2019
pubmed:
23
11
2019
medline:
4
5
2021
entrez:
23
11
2019
Statut:
ppublish
Résumé
The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis. It was recently shown that EEC progenitors contribute to intestinal epithelial growth and renewal, but the underlying mechanisms remain poorly understood. MicroRNAs are under-explored along the entire EEC lineage trajectory, and comparatively little is known about their contributions to intestinal homeostasis. We leverage unbiased sequencing and eight different mouse models and sorting methods to identify microRNAs enriched along the EEC lineage trajectory. We further characterize the functional role of EEC progenitor-enriched miRNA, miR-7, by in vivo dietary study as well as ex vivo enteroid in mice. First, we demonstrate that miR-7 is highly enriched across the entire EEC lineage trajectory and is the most enriched miRNA in EEC progenitors relative to Lgr5+ intestinal stem cells. Next, we show in vivo that in EEC progenitors miR-7 is dramatically suppressed under dietary conditions that favor crypt division and suppress EEC abundance. We then demonstrate by functional assays in mouse enteroids that miR-7 exerts robust control of growth, as determined by budding (proxy for crypt division), EdU and PH3 staining, and likely regulates EEC abundance also. Finally, we show by single-cell RNA sequencing analysis that miR-7 regulates Xiap in progenitor/stem cells and we demonstrate in enteroids that the effects of miR-7 on mouse enteroid growth depend in part on Xiap and Egfr signaling. This study demonstrates for the first time that EEC progenitor cell-enriched miR-7 is altered by dietary perturbations and that it regulates growth in enteroids via intact Xiap and Egfr signaling.
Sections du résumé
BACKGROUND & AIMS
The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis. It was recently shown that EEC progenitors contribute to intestinal epithelial growth and renewal, but the underlying mechanisms remain poorly understood. MicroRNAs are under-explored along the entire EEC lineage trajectory, and comparatively little is known about their contributions to intestinal homeostasis.
METHODS
We leverage unbiased sequencing and eight different mouse models and sorting methods to identify microRNAs enriched along the EEC lineage trajectory. We further characterize the functional role of EEC progenitor-enriched miRNA, miR-7, by in vivo dietary study as well as ex vivo enteroid in mice.
RESULTS
First, we demonstrate that miR-7 is highly enriched across the entire EEC lineage trajectory and is the most enriched miRNA in EEC progenitors relative to Lgr5+ intestinal stem cells. Next, we show in vivo that in EEC progenitors miR-7 is dramatically suppressed under dietary conditions that favor crypt division and suppress EEC abundance. We then demonstrate by functional assays in mouse enteroids that miR-7 exerts robust control of growth, as determined by budding (proxy for crypt division), EdU and PH3 staining, and likely regulates EEC abundance also. Finally, we show by single-cell RNA sequencing analysis that miR-7 regulates Xiap in progenitor/stem cells and we demonstrate in enteroids that the effects of miR-7 on mouse enteroid growth depend in part on Xiap and Egfr signaling.
CONCLUSIONS
This study demonstrates for the first time that EEC progenitor cell-enriched miR-7 is altered by dietary perturbations and that it regulates growth in enteroids via intact Xiap and Egfr signaling.
Identifiants
pubmed: 31756561
pii: S2352-345X(19)30156-0
doi: 10.1016/j.jcmgh.2019.11.001
pmc: PMC7021555
pii:
doi:
Substances chimiques
Birc4 protein, mouse
0
Inhibitor of Apoptosis Proteins
0
MIRN7 microRNA, mouse
0
MicroRNAs
0
EGFR protein, mouse
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
447-464Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK107634
Pays : United States
Organisme : NIDDK NIH HHS
ID : P01 DK094779
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG041198
Pays : United States
Organisme : NIH HHS
ID : K01 OD019911
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI116482
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK103141
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034933
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI132708
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK092776
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK085532
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK100508
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM089569
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI130379
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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