ANGPTL2 expression in the intestinal stem cell niche controls epithelial regeneration and homeostasis

The intestinal epithelium continually self‐renews and can rapidly regenerate after damage. Dysregulation of intestinal epithelial homeostasis leads to severe inflammatory bowel disease. Additionally, aberrant signaling by the secreted protein angiopoietin‐like protein 2 (ANGPTL2) causes chronic inflammation in a variety of diseases. However, little is known about the physiologic role of ANGPTL2 in normal tissue homeostasis and during wound repair following injury. Here, we assessed ANGPTL2 function in intestinal physiology and disease in vivo . Although intestinal development proceeded normally in Angptl2 ‐deficient mice, expression levels of the intestinal stem cell (ISC) marker gene Lgr5 decreased, which was associated with decreased transcriptional activity of β‐catenin in Angptl2 ‐deficient mice. Epithelial regeneration after injury was significantly impaired in Angptl2 ‐deficient relative to wild‐type mice. ANGPTL2 was expressed and functioned within the mesenchymal compartment cells known as intestinal subepithelial myofibroblasts (ISEMFs). ANGPTL2 derived from ISEMFs maintained the intestinal stem cell niche by modulating levels of competing signaling between bone morphogenetic protein (BMP) and β‐catenin. These results support the importance of ANGPTL2 in the stem cell niche in regulating stemness and epithelial wound healing in the intestine. Synopsis ANGPTL2 regulates stem cell activity and epithelial regeneration in the intestine. Intestinal subepithelial myofibroblasts secrete ANGPTL2 to maintain the intestinal stem cell niche by modulating proper BMP levels and β‐catenin signaling. ANGPTL2 is required for regeneration of intestinal epithelium after injury. ANGPTL2 is expressed in intestinal subepithelial myofibroblasts. Autocrine ANGPTL2 downregulates Bmp expression via integrin α5β1/NF‐κB signaling. Aberrant BMP signaling in Angptl2 ‐deficient mice decreases intestinal epithelial stem cell activity. Graphical Abstract ANGPTL2 is secreted upon intestinal injury and regulates the balance between β‐catenin and BMP signaling to promote intestinal stem cell maintenance and proliferation.