Cited by 263Inflammatory mediators and NSAID effectsInflammatory Bowel DiseasePeroxisome Proliferator-Activated Receptors

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Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury

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Brown, Sarah L., Riehl, Terrence E., Walker, Monica R., Geske, Michael J., Doherty, Jason M., Stenson, William F., Stappenbeck, Thaddeus S.·2007·Journal of Clinical Investigation

DOI 10.1172/jci29159PMC PMC1716207

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Abstract

We identified cellular and molecular mechanisms within the stem cell niche that control the activity of colonic epithelial progenitors (ColEPs) during injury. Here, we show that while WT mice maintained ColEP proliferation in the rectum following injury with dextran sodium sulfate, similarly treated Myd88(-/-) (TLR signaling-deficient) and prostaglandin-endoperoxide synthase 2(-/-) (Ptgs2(-/-)) mice exhibited a profound inhibition of epithelial proliferation and cellular organization within rectal crypts. Exogenous addition of 16,16-dimethyl PGE(2) (dmPGE(2)) rescued the effects of this injury in both knockout mouse strains, indicating that Myd88 signaling is upstream of Ptgs2 and PGE(2). In WT and Myd88(-/-) mice, Ptgs2 was expressed in scattered mesenchymal cells. Surprisingly, Ptgs2 expression was not regulated by injury. Rather, in WT mice, the combination of injury and Myd88 signaling led to the repositioning of a subset of the Ptgs2-expressing stromal cells from the mesenchyme surrounding the middle and upper crypts to an area surrounding the crypt base adjacent to ColEPs. These findings demonstrate that Myd88 and prostaglandin signaling pathways interact to preserve epithelial proliferation during injury using what we believe to be a previously undescribed mechanism requiring proper cellular mobilization within the crypt niche.

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Authors: Brown, S. L., Riehl, T. E., Walker, M. R., Geske, M. J., Doherty, J. M., Stenson, W. F., & Stappenbeck, T. S.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Stappenbeck, Thaddeus S.
ORCID: Geske, Michael J.
Doherty, Jason M.
Stappenbeck, Thaddeus S.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2007-01-02
Volume: 117
Issue: 1
Pages: 258-269
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci29159
PMC: PMC1716207
OpenAlex: W2145719229
Cited by: 263
References: 47
Citations by year: 2026: 7 · 2025: 5 · 2024: 9 · 2023: 7 · 2022: 3 · 2021: 13 · 2020: 8 · 2019: 6 · 2018: 13 · 2017: 14 · 2016: 10 · 2015: 10 · 2014: 15 · 2013: 16 · 2012: 18
FWCI: 19.15
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders: Crohn's and Colitis Foundation of America
Crohn's and Colitis Foundation
National Institutes of Health (DK-52574, DK55753, DK33165)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK033165, R03DK066220, P30 DK-52574, K08DK002954, DK55753, DK 02954, DK 33165, DK66220, R01DK055753, R37DK033165, P30DK052574)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: MyD88, cyclooxygenase-2, prostaglandin E2, intestinal stem cell niche, colonic injury, dextran sodium sulfate, Toll-like receptor signaling, epithelial cell proliferation, mesenchymal cells
MeSH terms: Animals, Cell Division, Intestinal Mucosa, Models, Genetic, Transcription, Genetic, Wounds and Injuries, Stromal Cells, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Mice, Cyclooxygenase 2, Myeloid Differentiation Factor 88

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Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury

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