Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury
Sarah L. Brown, … , William F. Stenson, Thaddeus S. Stappenbeck
Sarah L. Brown, … , William F. Stenson, Thaddeus S. Stappenbeck
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):258-269. https://doi.org/10.1172/JCI29159.
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Research Article

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

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 PGE2 (dmPGE2) rescued the effects of this injury in both knockout mouse strains, indicating that Myd88 signaling is upstream of Ptgs2 and PGE2. 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.

Authors

Sarah L. Brown, Terrence E. Riehl, Monica R. Walker, Michael J. Geske, Jason M. Doherty, William F. Stenson, Thaddeus S. Stappenbeck

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Figure 8

PSCs were closest to the crypt base epithelium in WT DSS-injured mice.

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PSCs were closest to the crypt base epithelium in WT DSS-injured mice. (...
(A–D and F–I) Sections of mouse rectums were stained with FITC-labeled anti–integrin α6 Ig (green) to label the basal surface of epithelial cells, bis-benzimide, and either (A–D) Zenon Alexa Fluor 594–labeled anti-Ptgs2 Ig (PSCs, red) or (F–I) Cy3-labeled anti–α-SMA Ig (myofibroblasts, red). Samples were taken from (A and F) WT untreated, (B and G) WT DSS-treated, (C and H) Myd88–/– untreated, and (D and I) Myd88–/– DSS-treated mice. The yellow dotted lines, which indicate minimum distance from the PSC or myofibroblasts to the base of the crypt epithelium (all views are of the crypt base only), measure 19 μm (A), 2 μm (B), 11 μm (C), 16 μm (D), 1.5 μm (F and I), 1.3 μm (G), and 1.7 μm (H). Quantification of distances between the crypt base and (E) PSCs and (J) anti–α-SMA–positive myofibroblasts. Mean values ± SEM were plotted for each group. An asterisk indicates a value that is statistically significantly different from the corresponding untreated control (*P < 0.001; Student’s t test).