PT  - JOURNAL ARTICLE
AU  - Osvaldo Contreras
AU  - Hesham Soliman
AU  - Marine Theret
AU  - Fabio M. Rossi
AU  - Enrique Brandan
TI  - Extracellular TGF-β downregulates the expression of Wnt transcription factor TCF7L2/TCF4 in mesenchymal stromal cells and fibroblasts
AID  - 10.1101/2020.01.05.895334
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.05.895334
4099  - http://biorxiv.org/content/early/2020/01/06/2020.01.05.895334.short
4100  - http://biorxiv.org/content/early/2020/01/06/2020.01.05.895334.full
AB  - Mesenchymal stromal cells (MSCs) are multipotent progenitors essential for organogenesis, tissue homeostasis, regeneration, and scar formation. Tissue injury upregulates TGF-β signaling, which plays predominant roles in MSCs fate, extracellular matrix (ECM) remodeling, and fibrogenesis. However, the molecular determinants of MSCs differentiation and survival are still poorly understood. The canonical Wnt Tcf/Lef transcription factors are important players in development and stem cell fate, but the mechanisms by which injury-induced signaling cues regulate the expression of Wnt Tcf/Lef remain poorly understood. Here, we studied the cell-specific gene expression of Tcf/Lef in MSCs and, more specifically, investigated whether damage-induced TGF-β affects the expression and function of TCF7L2 using different in vitro models of MSCs, including fibro-adipogenic progenitors. We demonstrated that Tcf/Lef members are differentially expressed in MSCs and that TGF-β signaling impairs TCF7L2 expression in these cells but not in myoblasts. Also, we show that the ubiquitin-proteasome system (UPS) regulates TCF7L2 proteostasis and participates in TGF-β-mediated TCF7L2 protein downregulation. Finally, we also show that TGF-β requires HDACs activity to repress the expression of TCF7L2 in fibroblasts. Thus, our work establishes a novel molecular interplay between TGF-β and Wnt signaling cascades in stromal cells and suggests that this mechanism could be targeted in tissue fibrosis.Summary statement TGF-β signaling suppresses the expression of the Wnt transcription factor TCF7L2 and compromises TCF7L2-dependent function in fibroblasts.CHXCycloheximideCTConnective tissueDMDDuchenne muscular dystrophyECMExtracellular matrixFAPsFibro-adipogenic progenitorsFACSFluorescence-activated cell sortingHDACsHistone deacetylasesMSCsMesenchymal stromal cellsMuSCsMuscle stem cellsMDMuscular dystrophyPDGFRαPlatelet-derived growth factor receptor alphaTcf/LefT-cell factor/lymphoid enhancerTFTranscription factorTGF-βTransforming growth factor type-betaTSATrichostatin ATNF-αTumor necrosis factor alphaUPSUbiquitin-proteasome system