Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
J Exp Med. 2011 Apr 11;208(4):677-88. doi: 10.1084/jem.20101737. Epub 2011 Mar 14.
The mammalian adult gastric epithelium self-renews continually through the activity of stem cells located in the isthmus of individual gland units. Mechanisms facilitating stomach stem and progenitor cell homeostasis are unknown. Here, we show that Notch signaling occurs in the mouse stomach epithelium during development and becomes restricted mainly to the isthmus in adult glands, akin to its known localization in the proliferative compartment of intestinal villi. Using genetic and chemical inhibition, we demonstrate that Notch signaling is required to maintain the gastric stem cell compartment. Activation of Notch signaling in lineage-committed stomach epithelial cells is sufficient to induce dedifferentiation into stem and/or multipotential progenitors that populate the mucosa with all major cell types. Prolonged Notch activation within dedifferentiated parietal cells eventually enhances cell proliferation and induces adenomas that show focal Wnt signaling. In contrast, Notch activation within native antral stomach stem cells does not affect cell proliferation. These results establish a role for Notch activity in the foregut and highlight the importance of cellular context in gastric tumorigenesis.
哺乳动物的成年胃上皮通过位于单个腺单位峡部的干细胞的活性不断自我更新。促进胃干细胞和祖细胞稳态的机制尚不清楚。在这里，我们显示 Notch 信号在小鼠胃上皮细胞的发育过程中发生，并在成年腺体内主要局限于峡部，类似于其在肠绒毛增殖区的已知定位。通过遗传和化学抑制，我们证明 Notch 信号对于维持胃干细胞区室是必需的。激活谱系定向的胃上皮细胞中的 Notch 信号足以诱导去分化为多能祖细胞，这些祖细胞可填充黏膜，形成所有主要细胞类型。在去分化的壁细胞中持续激活 Notch 最终会增强细胞增殖并诱导显示局部 Wnt 信号的腺瘤。相比之下，在天然的胃窦干细胞中激活 Notch 不会影响细胞增殖。这些结果确立了 Notch 活性在前肠中的作用，并强调了细胞背景在胃肿瘤发生中的重要性。
