Inflammation-induced epigenetic imprinting regulates intestinal stem cells
It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5<sup>+</sup> ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5<sup>+</sup> ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their 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 in a manner that persists and affects their sensitivity to adapt to future stress or challenges.
Authors
- Emma Lauder (ORCID: https://orcid.org/0000-0001-6619-4336)
- Robert Britton (ORCID: https://orcid.org/0000-0002-9335-0047)
- Visweswaran Ravikumar (ORCID: https://orcid.org/0000-0003-4670-3898)
- Katherine Y. King (ORCID: https://orcid.org/0000-0002-5093-6005)
- Robert R. Jenq (ORCID: https://orcid.org/0000-0002-5434-439X)
- Laure Maneix (ORCID: https://orcid.org/0000-0003-0044-5395)
- Katherine Oravecz-Wilson
- Chad J. Creighton (ORCID: https://orcid.org/0000-0002-6090-703X)
- Ana Santibanez
- Evan T. Keller (ORCID: https://orcid.org/0000-0002-7592-7535)
- Daniel C. Kraushaar
- Pavan R. Reddy (ORCID: https://orcid.org/0000-0001-7264-8429)
- Lu Li (ORCID: https://orcid.org/0000-0002-5496-7837)
- Yaping Sun (ORCID: https://orcid.org/0000-0003-0801-563X)
- Fengju Chen (ORCID: https://orcid.org/0000-0001-8744-9895)
- Arvind Rao
- Dongchang Zhao
- Tyler J Leach
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- University of Michigan (US)
- Michigan Medicine (US)
- Children's Cancer Center (US)
Publication Details
- Journal
- Cell stem cell
- Published
- 2024-09-03
- DOI
- https://doi.org/10.1016/j.stem.2024.08.006
- Citations
- 34
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 7.95
Funders
- Cancer Prevention and Research Institute of Texas
- University of Michigan
- National Institutes of Health
- National Cancer Institute