Wellcome Centre for Cell-Matrix Research and Manchester Breast Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Breast Cancer Res. 2018 Oct 22;20(1):128. doi: 10.1186/s13058-018-1048-1.
Stem cells are precursors for all mammary epithelia, including ductal and alveolar epithelia, and myoepithelial cells. In vivo mammary epithelia reside in a tissue context and interact with their milieu via receptors such as integrins. Extracellular matrix receptors coordinate important cellular signalling platforms, of which integrins are the central architects. We have previously shown that integrins are required for mammary epithelial development and function, including survival, cell cycle, and polarity, as well as for the expression of mammary-specific genes. In the present study we looked at the role of integrins in mammary epithelial stem cell self-renewal.
We used an in vitro stem cell assay with primary mouse mammary epithelial cells isolated from genetically altered mice. This involved a 3D organoid assay, providing an opportunity to distinguish the stem cell- or luminal progenitor-driven organoids as structures with solid or hollow appearances, respectively.
We demonstrate that integrins are essential for the maintenance and self-renewal of mammary epithelial stem cells. Moreover integrins activate the Rac1 signalling pathway in stem cells, which leads to the stimulation of a Wnt pathway, resulting in expression of β-catenin target genes such as Axin2 and Lef1.
Integrin/Rac signalling has a role in specifying the activation of a canonical Wnt pathway that is required for mammary epithelial stem cell self-renewal.
干细胞是所有乳腺上皮的前体细胞，包括导管和肺泡上皮以及肌上皮细胞。在体内，乳腺上皮细胞位于组织环境中，并通过整合素等受体与其微环境相互作用。细胞外基质受体协调重要的细胞信号平台，其中整合素是中央架构。我们之前已经表明，整合素对于乳腺上皮细胞的发育和功能是必需的，包括存活、细胞周期和极性，以及乳腺特异性基因的表达。在本研究中，我们研究了整合素在乳腺上皮干细胞自我更新中的作用。
我们使用了一种从基因改变的小鼠中分离的原代小鼠乳腺上皮细胞的体外干细胞测定法。这涉及到三维类器官测定法，为区分干细胞或腔前体细胞驱动的类器官提供了机会，分别为具有实心或空心外观的结构。
我们证明整合素对于乳腺上皮干细胞的维持和自我更新是必需的。此外，整合素在干细胞中激活 Rac1 信号通路，导致 Wnt 通路的激活，从而导致β-连环蛋白靶基因如 Axin2 和 Lef1 的表达。
整合素/Rac 信号在指定激活经典 Wnt 通路中起作用，该通路对于乳腺上皮干细胞的自我更新是必需的。
