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Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells.

ABSTRACT: The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that senses xenobiotics, diet, and gut microbial-derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5⁺ stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of sorted stem and progenitor cells, while AhR activation has the opposite effect. Moreover, intestinal-specific AhR knockout increases basal stem cell and crypt injury-induced cell proliferation and promotes colon tumorigenesis in a preclinical colitis-associated tumor model by upregulating FoxM1 signaling. Mechanistically, AhR transcriptionally suppresses FoxM1 expression. Activation of AhR in human organoids recapitulates phenotypes observed in mice, such as reduction in the percentage of colonic stem cells, promotion of stem cell differentiation, and attenuation of FoxM1 signaling. These findings indicate that the AhR-FoxM1 axis, at least in part, mediates colonic stem/progenitor cell behavior.

SUBMITTER: Han H

PROVIDER: S-EPMC7527924 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells.

Han Huajun H Davidson Laurie A LA Fan Yang-Yi YY Goldsby Jennifer S JS Yoon Grace G Jin Un-Ho UH Wright Gus A GA Landrock Kerstin K KK Weeks Bradley R BR Wright Rachel C RC Allred Clinton D CD Jayaraman Arul A Ivanov Ivan I Roper Jatin J Safe Stephen H SH Chapkin Robert S RS

The EMBO journal 20200810 19

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that senses xenobiotics, diet, and gut microbial-derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5<sup>+</sup> stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of ...[more]

PMID: 32915464

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Project description:BackgroundHuman epidemiological and animal studies suggest that developmental exposure to contaminants that activate the aryl hydrocarbon receptor (AHR) lead to suppression of immune system function throughout life. The persistence of immune deficiency throughout life suggests that the cellular target of AHR activation is a fetal hematopoietic progenitor or stem cell.ObjectivesThe aim of this study was to identify the effects of transplacental exposure to an AHR agonist on long-term self-renewal of fetal hematopoietic stem cells.MethodsPregnant C57BL/6 or AHR+/- mice were exposed to the AHR agonist, 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD). On day 14 of gestation, hematopoietic progenitors from wild-type or AHR-deficient fetuses were placed into in vitro T-lymphocyte differentiation cultures to identify the effects of transplacental TCDD on AHR activation in the fetus. We next analyzed the fetal hematopoietic progenitor cells for changes in reactive oxygen species (ROS). Finally, hematopoietic progenitors from fetuses exposed transplacentally to TCDD were mixed 1:1 with cells from congenic controls and used to reconstitute lethally irradiated recipients for analysis of long-term self-renewal potential.ResultsOur findings suggested that the effects of TCDD on the developing hematopoietic system were mediated by direct AHR activation in the fetus. Furthermore, developmental AHR activation by TCDD increased ROS in the fetal hematopoietic stem cells, and the elevated ROS was associated with a reduced capacity of the TCDD-exposed fetal cells to compete with control cells in a mixed competitive irradiation/reconstitution assay.ConclusionsOur findings indicate that AHR activation by TCDD in the fetus during pregnancy leads to impairment of long-term self-renewal of hematopoietic stem cells.CitationLaiosa MD, Tate ER, Ahrenhoerster LS, Chen Y, Wang D. 2016. Effects of developmental activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin on long-term self-renewal of murine hematopoietic stem cells. Environ Health Perspect 124:957-965; http://dx.doi.org/10.1289/ehp.1509820.

Dataset Information

Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells.

Publications

Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells.

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