Intestinal Foxl1⁺ cell-derived CXCL12 maintains epithelial homeostasis by modulating cellular metabolism

Several mesenchymal cell populations are known to regulate intestinal stem cell (ISC) self-renewal and differentiation. However, the influences of signaling mediators derived from mesenchymal cells other than ISC niche factors on epithelial homeostasis remain poorly understood. Here, we show that host and microbial metabolites, such as taurine and gamma-aminobutyric acid (GABA), act on PDGFRα^high Foxl1^high sub-epithelial mesenchymal cells to regulate their transcription. In addition, we found that CXC chemokine ligand 12 (CXCL12) produced from Foxl1^high sub-epithelial mesenchymal cells induces epithelial cell cycle arrest through modulation of the mevalonate–cholesterol synthesis pathway, which suppresses tumor progression in Apc^Min/+ mice. We identified that Foxl1^high subepithelial cells highly express CXCL12 among colonic mesenchymal cells. Foxl1-cre; Cxcl12^f/f mice showed an increased number of Ki67⁺ colonic epithelial cells. CXCL12-induced Ca²⁺ mobilization facilitated phosphorylation of AMPK in intestinal epithelial cells, which inhibits the maturation of sterol regulatory element-binding proteins (SREBPs) that are responsible for mevalonate pathway activation. Furthermore, Cxcl12 deficiency in Foxl1-expressing cells promoted tumor development in the small and large intestines of Apc^Min/+ mice. Collectively, these results demonstrate that CXCL12 secreted from Foxl1^high mesenchymal cells manipulates intestinal epithelial cell metabolism, which links to the prevention of tumor progression in Apc^Min/+ mice.