Wnt Signaling and Colorectal Cancer Group, The Beatson Institute for Cancer Research, Cancer Research UK, Glasgow, UK.
EMBO J. 2012 Oct 3;31(19):3901-17. doi: 10.1038/emboj.2012.248. Epub 2012 Sep 4.
The ability to regenerate following stress is a hallmark of self-renewing tissues. However, little is known about how regeneration differs from homeostatic tissue maintenance. Here, we study the role and regulation of Wingless (Wg)/Wnt signalling during intestinal regeneration using the Drosophila adult midgut. We show that Wg is produced by the intestinal epithelial compartment upon damage or stress and it is exclusively required for intestinal stem cell (ISC) proliferation during tissue regeneration. Reducing Wg or downstream signalling components from the intestinal epithelium blocked tissue regeneration. Importantly, we demonstrate that Wg from the undifferentiated progenitor cell, the enteroblast, is required for Myc-dependent ISC proliferation during regeneration. Similar to young regenerating tissues, ageing intestines required Wg and Myc for ISC hyperproliferation. Unexpectedly, our results demonstrate that epithelial but not mesenchymal Wg is essential for ISC proliferation in response to damage, while neither source of the ligand is solely responsible for ISC maintenance and tissue self-renewal in unchallenged tissues. Therefore, fine-tuning Wnt results in optimal balance between the ability to respond to stress without negatively affecting organismal viability.
在承受压力后能够进行再生是自我更新组织的一个标志。然而，人们对于再生与组织稳态维持之间的差异知之甚少。在这里，我们使用果蝇成年肠道研究了 Wingless（Wg）/Wnt 信号在肠道再生过程中的作用和调控。我们发现，Wg 在损伤或应激时由肠道上皮细胞产生，它在组织再生过程中对于肠道干细胞（ISC）的增殖是必需的。减少肠道上皮细胞中的 Wg 或下游信号成分会阻止组织再生。重要的是，我们证明了来自未分化祖细胞，即肠母细胞的 Wg，对于再生过程中 Myc 依赖性 ISC 增殖是必需的。与年轻的再生组织类似，衰老的肠道也需要 Wg 和 Myc 来促进 ISC 的过度增殖。出乎意料的是，我们的结果表明，上皮细胞而不是间充质细胞的 Wg 对于损伤后 ISC 的增殖是必需的，而配体的这两个来源都不能单独负责未受挑战的组织中的 ISC 维持和组织自我更新。因此，精细调节 Wnt 可以在不影响生物体生存能力的情况下，实现对压力做出反应的能力与最佳平衡。
