Home Sweet Home: a Foxl1+ Mesenchymal Niche for Intestinal Stem Cells

he intestinal epithelium undergoes rapid and conTstant renewal accomplished by intestinal stem cells (ISCs) every 3–5 days. ISCs divide and give rise to highly proliferative transit-amplifying progenitor cells that differentiate into the multiple differentiated cell types present in the crypt and villus. ISCs reside in a microenvironment surrounded by epithelial and underlying mesenchymal cells within the lamina propria populated by multiple cell types. Over the past decade, considerable advances have shown that the ISC niche is composed of molecular mediators that act in a paracrine or autocrine manner to maintain proper ISC behavior marked by self-renewal and multipotency. Within this niche, it is well established that Wnt and Notch signaling are active, bone morphogenic protein (BMP) signaling is inhibited, and that this collective regulation is essential for proper intestinal epithelial renewal. Blocking Wnt signaling by genetic deletion of Wnt pathway components or ectopic expression of Wnt antagonist Dickkopf-1 disrupts intestinal epithelial homeostasis, marked by crypt loss, decreased proliferation, and altered differentiation. Paneth cells (PCs) secrete Wnt and Notch ligands whereas mesenchymal cells secrete Wnts and Gremlin proteins (BMP antagonists). R-spondins, proteins that enhance basal Wnt signaling, may be important for ISC maintenance because R-spondins promote intestinal organoid growth in vitro, regulate Lgr5þ ISC in vivo, and are expressed in the intestinal stroma. However, the definitive identification of niche cell types responsible for ISC homeostasis has been elusive. It has been suggested that PCs are essential for the ISC niche based onWnt expression and support of in vitro ISC selfrenewal. However, subsequent studies in animal models lacking PCs showed no ISC dysfunction, suggesting that PCs are dispensable for ISC homeostasis. Conditional ablation of Porcn, required forWnt secretion, inmyosin heavy chain 11 (Myh11)-expressing myofibroblasts or villin-expressing epithelial cells, resulted in normal intestinal homeostasis, suggesting thatWnts from these cell types are not responsible for maintenance of ISCs and the intestinal epithelium. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Aoki et al showed that a subset of mesenchymal cells marked by the winged-helix transcription factor Foxl1 are critical inmaintaining ISC by contributing to the ISC niche. By using anti-Foxl1 antibodies and Foxl1-Cre; Rosa-mT/ mG mice, the investigators confirmed that Foxl1 marks a novel mesenchymal population that is closely apposed to crypts and is distinct from a-smooth muscle actin–positive andMyh11þ smoothmuscle cells andmyofibroblasts. Foxl1þ cells also express high levels of growth factors capable of inducing Wnt signaling such asWnt2b,Wnt5a, Rspo3, Grem1,