DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging.
Adolescent
Adult
Adult Stem Cells
/ cytology
Aged
Aged, 80 and over
Aging
/ genetics
Cells, Cultured
Child, Preschool
Colon
/ cytology
DNA Methylation
/ physiology
Epigenesis, Genetic
/ physiology
Humans
Infant
Infant, Newborn
Intestinal Mucosa
/ cytology
Intestine, Small
/ cytology
Middle Aged
Organoids
/ metabolism
Primary Cell Culture
Spheroids, Cellular
Young Adult
Aging
DNA Methylation
Epigenetic Clock
Intestinal Stem Cells
Organoids
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:
26
06
2019
revised:
22
11
2019
accepted:
25
11
2019
pubmed:
6
12
2019
medline:
4
5
2021
entrez:
6
12
2019
Statut:
ppublish
Résumé
The epithelia of the intestine and colon turn over rapidly and are maintained by adult stem cells at the base of crypts. Although the small intestine and colon have distinct, well-characterized physiological functions, it remains unclear if there are fundamental regional differences in stem cell behavior or region-dependent degenerative changes during aging. Mesenchyme-free organoids provide useful tools for investigating intestinal stem cell biology in vitro and have started to be used for investigating age-related changes in stem cell function. However, it is unknown whether organoids maintain hallmarks of age in the absence of an aging niche. We tested whether stem cell-enriched organoids preserved the DNA methylation-based aging profiles associated with the tissues and crypts from which they were derived. To address this, we used standard human methylation arrays and the human epigenetic clock as a biomarker of age to analyze in vitro-derived, 3-dimensional, stem cell-enriched intestinal organoids. We found that human stem cell-enriched organoids maintained segmental differences in methylation patterns and that age, as measured by the epigenetic clock, also was maintained in vitro. Surprisingly, we found that stem cell-enriched organoids derived from the small intestine showed striking epigenetic age reduction relative to organoids derived from colon. Our data validate the use of organoids as a model for studying human intestinal aging and introduce methods that can be used when modeling aging or age-onset diseases in vitro.
Sections du résumé
BACKGROUND & AIMS
The epithelia of the intestine and colon turn over rapidly and are maintained by adult stem cells at the base of crypts. Although the small intestine and colon have distinct, well-characterized physiological functions, it remains unclear if there are fundamental regional differences in stem cell behavior or region-dependent degenerative changes during aging. Mesenchyme-free organoids provide useful tools for investigating intestinal stem cell biology in vitro and have started to be used for investigating age-related changes in stem cell function. However, it is unknown whether organoids maintain hallmarks of age in the absence of an aging niche. We tested whether stem cell-enriched organoids preserved the DNA methylation-based aging profiles associated with the tissues and crypts from which they were derived.
METHODS
To address this, we used standard human methylation arrays and the human epigenetic clock as a biomarker of age to analyze in vitro-derived, 3-dimensional, stem cell-enriched intestinal organoids.
RESULTS
We found that human stem cell-enriched organoids maintained segmental differences in methylation patterns and that age, as measured by the epigenetic clock, also was maintained in vitro. Surprisingly, we found that stem cell-enriched organoids derived from the small intestine showed striking epigenetic age reduction relative to organoids derived from colon.
CONCLUSIONS
Our data validate the use of organoids as a model for studying human intestinal aging and introduce methods that can be used when modeling aging or age-onset diseases in vitro.
Identifiants
pubmed: 31805439
pii: S2352-345X(19)30168-7
doi: 10.1016/j.jcmgh.2019.11.013
pmc: PMC7044532
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
527-541Subventions
Organisme : NIDDK NIH HHS
ID : U01 DK085535
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG060908
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK085532
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK041301
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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