Endothelial and fibroblast niches are crucial for the homeostasis of epithelial organs. Fibroblasts play a central role in the stem cell niche and tumor microenvironment, and their interaction with epithelium has attracted great attentions. However, little is known about how endothelial cells influence the epithelium.

In a study published in Cell Reports and as a cover story, a research team led by Dr. ZENG Yi from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, reported a new regulation axis in which the endothelial cell-origin Wnts activate signaling in fibroblasts, which subsequently governs mammary epithelial branching.

The researchers generated a new fluorescent mouse model Axin2-mGFP, which reports Wnt/-catenin signaling activation in various organs including the intestine, hair follicle, cochlea, bladder, liver, and lung. Taking advantage of this reporter, researchers identified a subset of mGFP+ fibroblasts in the mammary gland. These cells resided close to the epithelium, align with blood vessels.

To investigate the heterotypic cell-cell interactions in vitro, they established a new mammary organoid system. The coculture of epithelium, mesenchyme and vasculature induced long and apparent mammary branches, recapitulating the cytoarchitecture of the mammary gland.

Deletion of either endothelial cells or fibroblasts led to reduced branching in organoids, suggesting these niche components are required for organizing mammary branching. Deletion of β-catenin in fibroblasts significantly reduced mammary branches in organoids and in vivo, revealing an essential role of fibroblast Wnt signaling activity in mammary epithelial branching.

Besides, the researchers revealed that the endothelial cell is the source of Wnt ligands that are responsible for fibroblast signaling. When wnt secretion was blocked in endothelial cells by Wntless gene deletion, Wnt/β-catenin signaling activity in fibroblasts was inhibited, consequently impeding branch formation in organoid and in vivo.

This study revealed a new signaling communication from endothelial cells to fibroblasts, which subsequently affects the epithelium. Endothelial cells act as an organizer for the complex and tightly regulated tissue microenvironment. It may have a broad implication to organs that consist of endothelial and mesenchymal niches.