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.

间充质基质细胞（MSCs）是器官发生，组织稳态，再生和疤痕形成必不可少的多能祖细胞。组织损伤会上调转化生长因子β（TGF-β）信号传导，从而调节成肌纤维细胞的命运，细胞外基质重塑和纤维化。但是，MSC分化和生存的分子决定因素仍然知之甚少。在经典的Wnt信号传导过程中，T细胞因子/淋巴增强因子（TCF / LEF）转录因子调节发育和干性，但损伤诱导的线索调节其表达的机制仍未得到充分研究。在这里，我们研究了TCF / LEF转录因子的细胞类型特异性基因表达，更具体地说，我们使用包括骨骼肌纤维成脂祖细胞在内的多种MSC模型研究了损伤诱导的TGF-β信号传导是否损害TCF7L2（也称为TCF4）的表达和功能。我们显示TCF / LEFs差异表达，并且TGF-β降低了MSCs中成纤维细胞中TCF7L2的表达。我们还发现，泛素-蛋白酶体系统调节TCF7L2蛋白稳态并参与TGF-β介导的TCF7L2蛋白下调。最后，我们证明TGF-β需要组蛋白脱乙酰基酶活性来抑制TCF7L2的表达。因此，我们的工作报告了TGF-β与PDGFRα中经典Wnt信号级联反应之间的新型相互作用 我们显示TCF / LEFs差异表达，并且TGF-β降低了MSCs中成纤维细胞中TCF7L2的表达。我们还发现，泛素-蛋白酶体系统调节TCF7L2蛋白稳态并参与TGF-β介导的TCF7L2蛋白下调。最后，我们证明TGF-β需要组蛋白脱乙酰基酶活性来抑制TCF7L2的表达。因此，我们的工作报告了TGF-β与PDGFRα中经典Wnt信号级联反应之间的新型相互作用 我们显示TCF / LEFs差异表达，并且TGF-β降低了MSCs中成纤维细胞中TCF7L2的表达。我们还发现，泛素-蛋白酶体系统调节TCF7L2蛋白稳态并参与TGF-β介导的TCF7L2蛋白下调。最后，我们证明TGF-β需要组蛋白脱乙酰基酶活性来抑制TCF7L2的表达。因此，我们的工作报告了TGF-β与PDGFRα中经典Wnt信号级联反应之间的新型相互作用⁺成纤维细胞，并暗示该机制可能针对组织修复和再生。