CXCL12 produced from Foxl1high mesenchymal cells modulates epithelial cell metabolism and prevents intestinal neoplasia (RNA-Seq)

Several mesenchymal cell populations are involved in the maintenance and differentiation of intestinal stem cells (ISCs) by secreting Wnts, R-spondins, and bone morphogenetic proteins. However, the influences of signaling mediators derived from mesenchymal cells other than ISC niche factors on epithelial homeostasis remain poorly understood. Here, we revealed that CXCL12 produced from Foxl1high sub-epithelial mesenchymal cells regulates epithelial cell proliferation through modulation of the mevalonate pathway, which contributes to prevention of tumorigenesis. Foxl1-cre; Cxcl12f/f mice showed increase in the number of Ki67+ proliferative cells in the colonic epithelium, which was decreased by treatment with mevalonate biogenesis inhibitor simvastatin. Moreover, Cxcl12 deficiency in Foxl1high mesenchymal cells promoted adenoma development in the colon and ileum of ApcMin/+ mice. Collectively, these results demonstrate the critical role of CXCL12 derived from Foxl1high sub-epithelial cells in prevention of intestinal neoplasia through modulation of cellular metabolism in epithelial cells.