Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Am J Physiol Gastrointest Liver Physiol. 2013 Aug 1;305(3):G241-9. doi: 10.1152/ajpgi.00480.2012. Epub 2013 Jun 6.
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.
硫酸乙酰肝素 (HS) 是 HS 蛋白聚糖 (HSPGs) 的组成部分，是一种存在于细胞表面的线性多糖。HSPGs 调节多种生长因子和信号分子的功能。我们使用小肠上皮细胞 (IEC) 特异性 HS 缺陷 C57Bl/6 小鼠，研究了小肠上皮 HS 是否在隐窝稳态中发挥某些作用。由于严重的肠道损伤，HS 缺陷小鼠的全身照射后存活率显着降低。HS 缺陷的 IEC 表现出 Wnt/β-catenin 途径破坏、β-catenin 核定位减少以及 Wnt 靶基因（包括隐窝再生过程中的 Lgr5）表达降低。此外，上皮 HS 增加了 IEC 对 Wnt 的结合亲和力，促进了 Wnt 辅助受体 LRP6 的磷酸化，并增强了 Wnt/β-catenin 信号转导，而在用 Wnt3a 进行离体刺激后，HS 缺陷型和野生型小鼠之间经典 Wnt 信号的激活相似直接抑制糖原合酶激酶-3β 后。因此，HS 影响 IEC 与 Wnt 的结合亲和力，从而促进经典 Wnt 信号的激活，并促进上皮损伤后小肠隐窝的再生。
