Language
English
Publication Date
10-3-2024
Journal
Cell Stem Cell
DOI
10.1016/j.stem.2024.08.006
PMID
39232559
PMCID
PMC11963838
PubMedCentral® Posted Date
10-3-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
It remains unknown whether, and how intestinal stem cells (ISC) adapt to inflammatory exposure, and if the adaptation leaves scars will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastrointestinal acute graft-versus-host disease (GI GVHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for in vivo regeneration despite resolution of the initial inflammatory exposure demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs that persists and affects their sensitivity to adapt to future stress or challenges.
Keywords
Animals, Inflammation, Epigenesis, Genetic, Stem Cells, Mice, Intestines, Genomic Imprinting, Mice, Inbred C57BL, Graft vs Host Disease, Regeneration, Cell Differentiation, Receptors, G-Protein-Coupled, Organoids
Published Open-Access
yes
Recommended Citation
Zhao, Dongchang; Ravikumar, Visweswaran; Leach, Tyler J; et al., "Inflammation-Induced Epigenetic Imprinting Regulates Intestinal Stem Cells" (2024). Faculty and Staff Publications. 3962.
https://digitalcommons.library.tmc.edu/baylor_docs/3962
Graphical Abstract