Cardiff School of Biosciences, European Cancer Stem Cell Research Institute, Cardiff, Wales, United Kingdom.
Department of Health and Applied Science, University of the West of England, Bristol, United Kingdom.
Stem Cells. 2018 Jan;36(1):114-122. doi: 10.1002/stem.2712. Epub 2017 Oct 13.
The importance of the Wnt-signaling pathway on the regulation and maintenance of the intestinal stem cell (ISC) population is well recognized. However, our current knowledge base is founded on models using systems of gross deregulation of the Wnt-signaling pathway. Given the importance of this signaling pathway on intestinal homeostasis, there is a need to explore the role of more subtle alterations in Wnt-signaling levels within this tissue. Herein, we have used a model of Apc2 loss to meet this aim. Apc2 is a homolog of Apc which can also form a destruction complex capable of binding β-catenin, albeit less efficiently than Apc. We show that systemic loss of Apc2 results in an increase in the number of cells displaying nuclear β-catenin at the base of the intestinal crypt. This subsequently impacts the expression levels of several ISC markers and the fitness of ISCs as assessed by organoid formation efficiency. This work provides the first evidence that the function and fitness of ISCs can be altered by even minor misregulation of the Wnt-signaling pathway. Our data highlights the importance of correct maintenance of this crucial signaling pathway in the maintenance and function of the ISC population. Stem Cells 2018;36:114-122.
Wnt 信号通路对肠道干细胞（ISC）群体的调节和维持的重要性已得到广泛认可。然而，我们目前的知识库是基于对 Wnt 信号通路严重失调的系统进行建模而建立的。鉴于该信号通路对肠道内稳态的重要性，有必要探索该组织中 Wnt 信号水平更细微变化的作用。为此，我们使用了 Apc2 缺失模型来满足这一目标。Apc2 是 Apc 的同源物，也可以形成能够结合β-连环蛋白的破坏复合物，尽管结合效率不如 Apc。我们发现，系统性缺失 Apc2 会导致肠隐窝底部显示核β-连环蛋白的细胞数量增加。这随后会影响几个 ISC 标志物的表达水平，以及 ISC 的适应性，这可通过类器官形成效率来评估。这项工作首次提供了证据，表明 Wnt 信号通路的轻微失调甚至可以改变 ISC 的功能和适应性。我们的数据强调了正确维持这一关键信号通路对于维持和功能的重要性ISC 群体。干细胞 2018;36:114-122。
