Growth Factor Regulation of Prostaglandin-Endoperoxide Synthase 2 (Ptgs2) Expression in Colonic Mesenchymal Stem Cells

Abstract

We previously found that a population of colonic stromal cells that constitutively express high levels of prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2) altered their location in the lamina propria in response to injury in a Myd88-dependent manner (Brown, S. L., Riehl, T. E., Walker, M. R., Geske, M. J., Doherty, J. M., Stenson, W. F., and Stappenbeck, T. S. (2007) J. Clin. Invest. 117, 258 -269). At the time of this study, the identity of these cells and the mechanism by which they expressed high levels of Ptgs2 were unknown. Here we found that these colonic stromal cells were mesenchymal stem cells (MSCs). These colonic MSCs expressed high Ptgs2 levels not through interaction with bacterial products but instead as a consequence of mRNA stabilization downstream of Fgf9 (fibroblast growth factor 9), a growth factor that is constitutively expressed by the intestinal epithelium. This stabilization was mediated partially through a mechanism involving endogenous CUG-binding protein 2 (CUGbp2). These studies suggest that Fgf9 is an important factor in the regulation of Ptgs2 in colonic MSCs and may be a factor involved in its constitutive expression in vivo.

Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis

“…The purpose would be to find and utilize MSCs with the highest VEGF expression. For example, global gene analysis of MSCs isolated from mice showed that cMSCs produce more Vegf mRNA than bone marrow MSCs (34). It is likely that cMSCs produce other proangiogenic or prohealing factors that work via other pathways, but our results suggest that MSCs are most effective for mucosal wound healing when injected intramucosally and that VEGF expression/angiogenesis plays an important part in mucosal repair.…”

“…This level of knockdown is relevant, as mice that are heterozygous for Vegf are not viable due to the exquisite dose dependency of VEGF (29). Nontargeting and VEGF shRNA lines maintained cell surface markers consistent with those of cMSCs (Supplemental Figure 17) (34). We found that the minimal number of nontargeting shRNA cMSCs that rescued muscle necrosis in injured Ptgir -/-mice was 3 × 10 5 injected cells ( Figure 6B).…”

“…We hypothesized that MSCs could be a potential cellular therapy because they express high levels of VEGF in culture relative to other growth factors and cytokines (33). We chose to use MSCs isolated from the colon in our studies because they have higher levels of VEGF expression as compared with MSCs isolated from the bone marrow (34).…”

“…Isolation of cMSCs cMSCs were isolated from WT or CMV immediate enhancer/β-actin promoter GFP mice (The Jackson Laboratory) using a protocol adapted from a previous study (34). Briefly, the colons were removed, flushed, minced, and treated with media containing 1 mM DTT for 20 minutes to remove epithelial cells.…”

MyD88 signaling promotes both mucosal homeostatic and fibrotic responses during Salmonella-induced colitis

“…Instead, they reported a MyD88-dependent repositioning of Cox-2-expressing stromal cells of unknown identity toward colonic epithelial progenitor cells located at the base of colonic crypts. In a recent study, this group determined that these colonic stromal Cox-2-positive cells are mesenchymal stem cells (38). This repositioning was required to maintain epithelial cell proliferation in response to injury.…”