Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection
Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection
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DOI：
10.1152/ajpgi.00426.2005
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发表时间：
2006-06-01
影响因子：
4.5
通讯作者：
Rubin, Deborah C.
中科院分区：
文献类型：
--
作者：
Tang, Yuzhu;Swietlicki, Elzbieta A.;Rubin, Deborah C.
肠上皮在功能性小肠表面积丧失后经历显著的适应性反应，其特征在于增加的隐窝细胞增殖和增加的肠上皮细胞从隐窝向绒毛尖端的迁移，导致绒毛增生和增强的营养吸收。Hedgehog（Hh）信号在调节胚胎肠形态发生期间上皮-间充质相互作用方面发挥着关键作用。我们以前的研究表明，在新生小鼠中阻断Hh信号导致小肠上皮隐窝细胞增殖增加和肠上皮细胞脂肪吸收和形态改变。hh家族成员也在成人肠道中表达，但其在成熟小肠中的作用尚不清楚。使用部分小肠切除后的肠适应模型，通过确定阻断Hh信号传导对功能性表面积损失后的再生反应的影响来检查Hh信号传导在成人肠道中的作用。将hh失活单克隆抗体或对照抗体给予持续50%肠切除的小鼠。术前回肠定量实时PCR的mRNA分析显示，印度刺猬是最丰富的Hh家族成员。Hh受体Patched比Patched 2更丰富。对Hh信号传导的下游靶点的分析表明，Gli3的丰度是Gli1和Gli2的两倍，骨形态发生蛋白（BMP）2的表达最高，与BMP 1、-4和-7相比。肠切除后，Hh，补丁，Gli，和大多数BMP基因的表达显着下调，在残余回肠，并在抗Hh抗体治疗的小鼠，补丁2和Gli 1的表达进一步抑制。在Hh抗体治疗的小鼠切除后，肠上皮细胞从隐窝到绒毛尖的迁移率增加，并在术后2周，适应性肠道细胞凋亡增加。然而，隐窝细胞增殖，绒毛高度和隐窝深度没有增加。这些数据表明，Hh信号通过调节上皮细胞从隐窝向绒毛尖的迁移和通过增强细胞凋亡在成人肠上皮稳态中起作用。
The intestinal epithelium undergoes a marked adaptive response following loss of functional small bowel surface area characterized by increased crypt cell proliferation and increased enterocyte migration from crypt to villus tip, resulting in villus hyperplasia and enhanced nutrient absorption. Hedgehog (Hh) signaling plays a critical role in regulating epithelial-mesenchymal interactions during morphogenesis of the embryonic intestine. Our previous studies showed that blocking Hh signaling in neonatal mice results in increased small intestinal epithelial crypt cell proliferation and altered enterocyte fat absorption and morphology. Hh family members are also expressed in the adult intestine, but their role in the mature small bowel is unclear. With the use of a model of intestinal adaptation following partial small bowel resection, the role of Hh signaling in the adult gut was examined by determining the effects of blocking Hh signaling on the regenerative response following loss of functional surface area. Hh-inactivating monoclonal antibodies or control antibodies were administered to mice that sustained a 50% intestinal resection. mRNA analyses of the preoperative ileum by quantitative real-time PCR revealed that Indian hedgehog was the most abundant Hh family member. The Hh receptor Patched was more abundant than Patched 2. Analyses of downstream targets of Hh signaling demonstrated that Gli3 was twofold more abundant than Gli1 and Gli2 and that bone morphogenetic protein (BMP)2 was most highly expressed compared with BMP1, -4, and -7. Following intestinal resection, the expression of Hh, Patched, Gli, and most BMP genes was markedly downregulated in the remnant ileum, and, in anti-Hh antibody-treated mice, expression of Patched 2 and Gli 1 was further suppressed. In Hh antibody-treated mice following resection, the enterocyte migration rate from crypt to villus tip was increased, and by 2 wk postoperation, apoptosis was increased in the adaptive gut. However, crypt cell proliferation, villus height, and crypt depth were not augmented. These data indicate that Hh signaling plays a role in adult gut epithelial homeostasis by regulating epithelial cell migration from crypt to villus tip and by enhancing apoptosis.