TGF-β-driven downregulation of the transcription factor TCF7L2 affects Wnt/β-catenin signaling in PDGFRα + fibroblasts

J Cell Sci. 2020 Jun 19;133(12):jcs242297. doi: 10.1242/jcs.242297.

Abstract

Mesenchymal stromal cells (MSCs) are multipotent progenitors essential for organogenesis, tissue homeostasis, regeneration and scar formation. Tissue injury upregulates transforming growth factor β (TGF-β) signaling, which modulates myofibroblast fate, extracellular matrix remodeling and fibrosis. However, the molecular determinants of MSC differentiation and survival remain poorly understood. During canonical Wnt signaling, T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors regulate development and stemness, but the mechanisms by which injury-induced cues modulate their expression remain underexplored. Here, we studied the cell type-specific gene expression of TCF/LEF transcription factors and, more specifically, we investigated whether damage-induced TGF-β signaling impairs the expression and function of TCF7L2 (also known as TCF4), using several models of MSCs, including skeletal muscle fibro-adipogenic progenitors. We show that TCF/LEFs are differentially expressed and that TGF-β reduces the expression of TCF7L2 in MSCs but not in myoblasts. We also found that the ubiquitin-proteasome system regulates TCF7L2 proteostasis and participates in TGF-β-mediated TCF7L2 protein downregulation. Finally, we show that TGF-β requires histone deacetylase activity to repress the expression of TCF7L2. Thus, our work reports a novel interplay between TGF-β and canonical Wnt signaling cascades in PDGFRα+ fibroblasts and suggests that this mechanism could be targeted in tissue repair and regeneration.

Keywords: MSCs; Myoblasts; Myofibroblasts; PDGFRα; Regeneration; Stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Down-Regulation
  • Fibroblasts / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha
  • Transcription Factors
  • Transforming Growth Factor beta* / metabolism
  • Wnt Signaling Pathway*
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Transcription Factors
  • Transforming Growth Factor beta
  • beta Catenin
  • Receptor, Platelet-Derived Growth Factor alpha