Extracellular TGF-β downregulates the expression of Wnt transcription factor TCF7L2/TCF4 in mesenchymal stromal cells and fibroblasts

Mesenchymal stromal/stem cells (MSCs) are multipotent progenitors essential ororganogenesis, tissue homeostasis, regeneration, and scar formation. Tissue injury upregulates TGF-{beta} signaling, which modulates myofibroblast fate, extracellular matrix remodeling, and fibrosis. However, the molecular determinants of MSCs differentiation and survival remain poorly understood. The canonical Wnt 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-specific gene expression of Tcf/Lef and, more specifically, we investigated whether damage-induced TGF-{beta} impairs the expression and function of TCF7L2, 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 HDACs activity to repress the expression of TCF7L2. Thus, our work found a novel interplay between TGF-{beta} and Wnt canonical signaling cascades in PDGFR+ fibroblasts and suggests that this mechanism could be targeted in tissue repa ir and regeneration. Summary statementTGF-{beta} signaling suppresses the expression of the Wnt transcription factor TCF7L2 and compromises TCF7L2-dependent functions in tissue-resident PDGFR+ fibroblasts.