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 6

PSCs are CD44+ stromal cells.

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PSCs are CD44+ stromal cells. (A–I) Double-labeled, immu...
(A–I) Double-labeled, immunofluorescence-stained rectal sections from a WT DSS-treated mouse. (A–C) Sections stained with Zenon Alexa Fluor 594–labeled anti-Ptgs2 Ig (Invitrogen) (PSCs, red), FITC-labeled anti-CD44 Ig (green), and bis-benzimide (blue). All PSCs show membrane staining for CD44. Arrowheads denote CD44+ epithelial cells in the crypt base. (A) Ptgs2, (B) CD44, and (C) merged image of A and B. (D–F) Two crypt bases from a section stained with Zenon Alexa Fluor 594–labeled anti-Ptgs2 Ig (PSCs, red) and FITC-labeled anti-CD45 Ig (leukocytes, green). (D) Ptgs2, (E) CD45, and (F) merged images (upper panel shows a CD45– PSC, and lower panel shows a weakly CD45+ PSC). The arrowhead denotes the position of a CD45+ intraepithelial lymphocyte. (G–I) Section stained with (G) Zenon Alexa Fluor 594–labeled anti-Ptgs2 Ig (PSCs) and (H) FITC-labeled anti-F4/80 Ig (macrophages, green). (I) Merged image of G and H. The PSCs in the rectal mesenchyme did not colocalize with this or any other marker of differentiated hematopoietic cell lineages. In all panels, the arrows indicate the position of PSCs, and the yellow dashed lines indicate the crypt epithelial base. Scale bars: 20 μm.