Endothelial and fibroblast niches are crucial for epithelial organs. How these heterotypic cells interact is of great interest. In this study, we reveal an axis of signaling in which fibroblasts relay Wnt signals from the endothelial niche to organize epithelial patterning. We generate an Axin2-membrane GFP (mGFP) reporter mouse and observe robust Wnt/β-catenin signaling activities in fibroblasts surrounding the mammary epithelium. To enable cell-type-specific gene manipulation in vitro, we establish an organoid system via coculture of endothelial cells (ECs), fibroblasts, and mammary epithelial cells. Deletion of β-catenin in fibroblasts impedes epithelium branching, and ECs are responsible for the activation of Wnt/β-catenin signaling in fibroblasts. In vivo, EC deletion of Wntless inhibits Wnt/β-catenin signaling activity in fibroblasts, rendering a reduction in epithelial branches. These findings highlight the significance of the endothelial niche in tissue patterning, shedding light on the interactive mechanisms in which distinct niche components orchestrate epithelial organogenesis and tissue homeostasis.

内皮细胞和成纤维细胞微环境对于上皮器官至关重要。这些异型细胞如何相互作用引起了人们的极大兴趣。在这项研究中，我们揭示了一个信号轴，其中成纤维细胞传递来自内皮微环境的 Wnt 信号来组织上皮图案。我们生成了Axin2膜 GFP (mGFP) 报告小鼠，并观察乳腺上皮周围成纤维细胞中强大的 Wnt/β-连环蛋白信号传导活动。为了能够在体外进行细胞类型特异性基因操作，我们通过内皮细胞（EC）、成纤维细胞和乳腺上皮细胞的共培养建立了一个类器官系统。成纤维细胞中β-连环蛋白的缺失会阻碍上皮分支，而 EC 负责成纤维细胞中 Wnt/β-连环蛋白信号的激活。在体内，Wntless 的 EC 缺失会抑制成纤维细胞中的 Wnt/β-catenin 信号传导活性，导致上皮分支减少。这些发现强调了内皮生态位在组织模式中的重要性，揭示了不同生态位成分协调上皮器官发生和组织稳态的相互作用机制。