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

Mesenchymal stromal cells (MSCs) are multipotent progenitors essential for organogenesis, tissue homeostasis, regeneration and scar formation. Tissue injury upregulates transforming growth factor beta (TGF-beta) 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-beta 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-beta 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-beta-mediated TCF7L2 protein downregulation. Finally, we show that TGF-beta requires histone deacetylase activity to repress the expression of TCF7L2. Thus, our work reports a novel interplay between TGF-beta and canonical Wnt signaling cascades in PDGFR alpha(+) fibroblasts and suggests that this mechanism could be targeted in tissue repair and regeneration.