Prostaglandin E2 promotes intestinal repair through an adaptive cellular response of the epithelium

Abstract

Adaptive cellular responses are often required during wound repair. Following disruption of the intestinal epithelium, wound-associated epithelial (WAE) cells form the initial barrier over the wound. Our goal was to determine the critical factor that promotes WAE cell differentiation. Using an adaptation of our in vitro primary epithelial cell culture system, we found that prostaglandin E2 (PGE 2 ) signaling through one of its receptors, Ptger4, was sufficient to drive a differentiation state morphologically and transcriptionally similar to in vivo WAE cells. WAE cell differentiation was a permanent state and dominant over enterocyte differentiation in plasticity experiments. WAE cell differentiation was triggered by nuclear b-catenin signaling independent of canonical Wnt signaling. Creation of WAE cells via the PGE 2 -Ptger4 pathway was required in vivo, as mice with loss of Ptger4 in the intestinal epithelium did not produce WAE cells and exhibited impaired wound repair. Our results demonstrate a mechanism by which WAE cells are formed by PGE 2 and suggest a process of adaptive cellular reprogramming of the intestinal epithelium that occurs to ensure proper repair to injury.

Temporal Regulation of the Bacterial Metabolite Deoxycholate during Colonic Repair Is Critical for Crypt Regeneration

“…A defining feature of barrier re-establishment is the formation of a monolayer of post-mitotic WAE cells that are produced by stem/progenitor cells in crypts adjacent to wound (Figure S1A) (Manieri et al, 2012). WAE cell formation is dependent on PGE2 signaling to the epithelium through PTGER4 (Miyoshi et al, 2017). The next phase (days~4–8) is wound channel formation.…”

“…To further test the role of timing, we performed DCA reconstitution from day 0-day 3 in vancomycin pre-treated mice and analyzed wounds at day 4 post-injury. We used a previously established method of analyzing wounds at day 4 from whole mount images (Miyoshi et al, 2017) and found that this treatment significantly impaired barrier re-establishment associated with reduced PGE2 levels (Figure S5C–E). Taken together, these findings confirm that the timing of DCA generation is crucial for transition from barrier re-establishment to crypt regeneration.…”

“…Upon injury of this barrier, a cascade of coordinated events occurs in distinct phases involving multiple host cell types and molecules they produce that ensure efficient and complete repair (Leoni et al, 2015b). Important aspects of repair are the control of intestinal epithelial stem and progenitor proliferation in crypts of Lieberkühn, alteration of intestinal epithelial differentiation programs, and changes in cellular migration/tropism of epithelial cells and mobilizable populations of stromal and immune cells (Brown et al, 2007; Manieri et al, 2012; Miyoshi et al, 2012; Miyoshi et al, 2017). It is clear that the luminal microbiota can alter each of these host processes involved in repair, but the signaling pathways and coordination between host and microbes is not well understood (Leoni et al, 2015b).…”

“…In particular, PTGS2-expressing mesenchymal stem cells localize specifically in the colonic wound bed in close association with the crypts adjacent to the wound (Brown et al, 2007; Manieri et al, 2012). PGE2 secreted from these cells acts through its receptor PTGER4 on intestinal epithelial cells, to stimulate WAE differentiation (Miyoshi et al, 2017). Further support for the role of microbiota comes from a recent finding suggesting that an inflammatory environment during injury changes the microbiota composition near the site of the wound bed, including enrichment of Akkermansia muciniphilia , to enhance initial wound closure (Alam et al, 2016).…”

“…We previously found that enhanced PGE2 signaling in epithelial cells is critical for barrier re-establishment (Miyoshi et al, 2017). In the present study, we first demonstrated that the subsequent down modulation of PGE2 is necessary to permit the second phase of repair to proceed.…”