Contreras Osvaldo, Soliman Hesham, Theret Marine, Rossi Fabio M V, Brandan Enrique
Departamento de Biología Celular y Molecular and Center for Aging and Regeneration (CARE-ChileUC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile
Biomedical Research Centre, Department of Medical Genetics and School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
J Cell Sci. 2020 Jun 19;133(12):jcs242297. doi: 10.1242/jcs.242297.
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、再生和瘢痕形成所必需的多能祖细胞。组织损伤会上调转化生长因子β（TGF-β）信号传导，该信号传导调节肌成纤维细胞命运、细胞外基质重塑和纤维化。然而，MSCs分化和存活的分子决定因素仍知之甚少。在经典Wnt信号传导过程中，T细胞因子/淋巴样增强因子（TCF/LEF）转录因子调节发育和干性，但损伤诱导的信号调节其表达的机制仍未得到充分探索。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脂肪生成祖细胞在内的几种MSCs模型，研究了损伤诱导的TGF-β信号传导是否会损害TCF7L2（也称为TCF4）的表达和功能。我们表明，TCF/LEF表达存在差异，并且TGF-β降低了MSCs中TCF7L2的表达，但在成肌细胞中没有。我们还发现泛素-蛋白酶体系统调节TCF7L2的蛋白质稳态，并参与TGF-β介导的TCF7L2蛋白下调。最后，我们表明TGF-β需要组蛋白脱乙酰酶活性来抑制TCF7L2的表达。因此，我们的工作报道了PDGFRα成纤维细胞中TGF-β与经典Wnt信号级联之间的一种新的相互作用，并表明这种机制可能是组织修复和再生的靶点。
