Distinct fibroblast subsets regulate lacteal integrity through YAP/TAZ-induced VEGF-C in intestinal villi

Nat Commun. 2020 Aug 14;11(1):4102. doi: 10.1038/s41467-020-17886-y.

Abstract

Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFRβ+ IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake. Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment. Our findings demonstrate the heterogeneity of IntSCs and reveal that distinct subsets of villi fibroblasts regulate lacteal integrity through YAP/TAZ-induced VEGF-C secretion, providing new insights into the dynamic regulatory mechanisms behind lymphangiogenesis and lymphatic remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cells, Cultured
  • Cluster Analysis
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / metabolism*
  • Fibroblasts / ultrastructure
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • In Situ Hybridization, Fluorescence
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / ultrastructure
  • Lymphangiogenesis / genetics
  • Lymphangiogenesis / physiology
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron
  • Neovascularization, Physiologic / genetics
  • Neovascularization, Physiologic / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism*
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Transcription Factors
  • Vascular Endothelial Growth Factor C
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Acyltransferases
  • tafazzin protein, mouse