Endothelial Wnts control mammary epithelial patterning via fibroblast signaling

Cell Rep. 2021 Mar 30;34(13):108897. doi: 10.1016/j.celrep.2021.108897.

Abstract

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.

Keywords: Axin2; Wnt/β-catenin signaling; endothelial cells; fibroblasts; niche.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axin Protein / metabolism
  • Body Patterning*
  • Endothelial Cells / metabolism*
  • Epithelium / metabolism*
  • Estrous Cycle
  • Female
  • Fibroblasts / metabolism*
  • Fluorescence
  • Genes, Reporter
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Mammary Glands, Animal / growth & development*
  • Mammary Glands, Animal / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway*
  • beta Catenin / metabolism

Substances

  • Axin Protein
  • Axin2 protein, mouse
  • Wnt Proteins
  • beta Catenin
  • Green Fluorescent Proteins