Hedgehog signaling controls homeostasis of adult intestinal smooth muscle.
Hedgehog signaling controls homeostasis of adult intestinal smooth muscle.
复制标题
DOI：
10.1016/j.ydbio.2011.04.025
复制
发表时间：
2011-07-01
影响因子：
2.7
通讯作者：
Gumucio DL
中科院分区：
文献类型：
--
作者：
Zacharias WJ;Madison BB;Kretovich KE;Walton KD;Richards N;Udager AM;Li X;Gumucio DL
Hedgehog（Hh）通路在哺乳动物胃肠道发育过程中发挥着多种模式化作用，但其在成年肠道功能中的作用尚未得到广泛研究。在这里，我们表明，慢性减少联合上皮印度（Ihh）和声波（Shh）刺猬信号导致肠上皮下肌成纤维细胞的错误定位，绒毛核心和粘膜肌层平滑肌的损失，以及隐窝增生。相反，Ihh在肠上皮细胞中的慢性过度表达导致绒毛平滑肌的进行性扩张，但不会导致上皮细胞增殖减少。总之，这些小鼠模型表明，在成人肠固有层中的平滑肌群体是高度敏感的Hh配体的水平。我们进一步证明，Hh配体驱动原代肠间充质培养物中的平滑肌分化，C3 H10 T1/2细胞中的细胞自主Hh信号转导激活平滑肌主调节因子myocardin（Myocd）并诱导平滑肌分化。Hh配体激活Myocd的快速动力学以及该基因中不寻常浓度的Gli sties的存在表明Hh可能直接调节Myocd。因此，这些数据表明，Hh是成人肠平滑肌稳态的关键调节剂，并表明Hh信号传导和Myocd激活之间的重要联系。此外，数据支持的想法，降低Hh信号促进隐窝扩张和增加上皮细胞增殖，但表明慢性增加Hh配体水平不抑制隐窝增殖，如先前提出的。
The Hedgehog (Hh) pathway plays multiple patterning roles during development of the mammalian gastrointestinal tract, but its role in adult gut function has not been extensively examined. Here we show that chronic reduction in the combined epithelial Indian (Ihh) and Sonic (Shh) hedgehog signal leads to mislocalization of intestinal subepithelial myofibroblasts, loss of smooth muscle in villus cores and muscularis mucosa as well as crypt hyperplasia. In contrast, chronic over-expression of Ihh in the intestinal epithelium leads to progressive expansion of villus smooth muscle, but does not result in reduced epithelial proliferation. Together, these mouse models show that smooth muscle populations in the adult intestinal lamina propria are highly sensitive to the level of Hh ligand. We demonstrate further that Hh ligand drives smooth muscle differentiation in primary intestinal mesenchyme cultures and that cell-autonomous Hh signal transduction in C3H10T1/2 cells activates the smooth muscle master regulator myocardin (Myocd) and induces smooth muscle differentiation. The rapid kinetics of Myocd activation by Hh ligands as well as the presence of an unusual concentration of Gli sties in this gene suggest that regulation of Myocd by Hh might be direct. Thus, these data indicate that Hh is a critical regulator of adult intestinal smooth muscle homeostasis and suggest an important link between Hh signaling and Myocd activation. Moreover, the data support the idea that lowered Hh signals promote crypt expansion and increased epithelial cell proliferation, but indicate that chronically increased Hh ligand levels do not dampen crypt proliferation as previously proposed.