title: Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/β-catenin signaling.
abstract: Heparan sulfate (HS), a constituent of HS proteoglycans (HSPGs), is a linear polysaccharide present on the cell surface. HSPGs modulate functions of several growth factors and signaling molecules. We examined whether small intestinal epithelial HS plays some roles in crypt homeostasis using intestinal epithelium cell (IEC)-specific HS-deficient C57Bl/6 mice. Survival rate after total body irradiation was significantly reduced in HS-deficient mice due to profound intestinal injury. HS-deficient IECs exhibited Wnt/β-catenin pathway disruption, decreased levels of β-catenin nuclear localization, and reduced expression of Wnt target genes, including Lgr5 during crypt regeneration. Moreover, epithelial HS increased Wnt binding affinity of IECs, promoted phosphorylation of Wnt coreceptor LRP6, and enhanced Wnt/β-catenin signaling following ex vivo stimulation with Wnt3a, whereas activation of canonical Wnt signaling following direct inhibition of glycogen synthase kinase-3β by lithium chloride was similar between HS-deficient and wild-type mice. Thus HS influences the binding affinity of IECs to Wnt, thereby promoting activation of canonical Wnt signaling and facilitating regeneration of small intestinal crypts after epithelial injury.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakase
authors.forename: Minoru
authors.initials: M
authors.lastname: Matsuura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Honzawa
authors.forename: Kayoko
authors.initials: K
authors.lastname: Matsumura
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Uza
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Emiko
authors.initials: E
authors.lastname: Mizoguchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000818:Animals; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000172:deficiency* / Q000502:physiology*; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000473:pathology* / Q000503:physiopathology* / Q000528:radiation effects; D007421:Intestine, Small / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000502:physiology; D014916:Whole-Body Irradiation; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000378:metabolism
chemical_list: D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D060509:Wnt3A Protein
keywords: Wnt signaling; heparan sulfate; intestinal regeneration