title: ANGPTL2 expression in the intestinal stem cell niche controls epithelial regeneration and homeostasis.
abstract: 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 diseasein vivoAlthough intestinal development proceeded normally inAngptl2-deficient mice, expression levels of the intestinal stem cell (ISC) marker geneLgr5decreased, which was associated with decreased transcriptional activity of β-catenin inAngptl2-deficient mice. Epithelial regeneration after injury was significantly impaired inAngptl2-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.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical sciences, Kumamoto University, Chuo-ku Kumamoto, Japan horiguti@kumamoto-u.ac.jp enmoto@gpo.kumamoto-u.ac.jp oike@gpo.kumamoto-u.ac.jp.|Institute of Resource Development and Analysis, Kumamoto University, Chuo-ku Kumamoto, Japan.
authors.forename: Haruki
authors.identifier: 0000-0001-9344-8362
authors.initials: H
authors.lastname: Horiguchi
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical sciences, Kumamoto University, Chuo-ku Kumamoto, Japan horiguti@kumamoto-u.ac.jp enmoto@gpo.kumamoto-u.ac.jp oike@gpo.kumamoto-u.ac.jp.
authors.forename: Motoyoshi
authors.identifier: 0000-0002-8287-2456
authors.initials: M
authors.lastname: Endo
authors.affiliation: Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku Kyoto, Japan.
authors.forename: Kohki
authors.initials: K
authors.lastname: Kawane
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical sciences, Kumamoto University, Chuo-ku Kumamoto, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kadomatsu
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical sciences, Kumamoto University, Chuo-ku Kumamoto, Japan.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Terada
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical sciences, Kumamoto University, Chuo-ku Kumamoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Morinaga
authors.affiliation: Institute of Resource Development and Analysis, Kumamoto University, Chuo-ku Kumamoto, Japan.
authors.forename: Kimi
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical sciences, Kumamoto University, Chuo-ku Kumamoto, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical sciences, Kumamoto University, Chuo-ku Kumamoto, Japan horiguti@kumamoto-u.ac.jp enmoto@gpo.kumamoto-u.ac.jp oike@gpo.kumamoto-u.ac.jp.
authors.forename: Yuichi
authors.identifier: 0000-0003-3245-5395
authors.initials: Y
authors.lastname: Oike
mesh_terms: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000096:biosynthesis* / Q000172:deficiency; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000293:injuries* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000032:analysis; D012038:Regeneration; D055153:Stem Cell Niche; D014945:Wound Healing; D051176:beta Catenin / Q000032:analysis
chemical_list: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; C495267:CTNNB1 protein, mouse; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin
keywords: 
  BMP
  ; 
  ISEMF
  ; ANGPTL2; homeostasis; regeneration