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, V6T 1Z3 Vancouver, BC, Canada.
J Cell Sci. 2019 Oct 9;132(19):jcs232157. doi: 10.1242/jcs.232157.
Fibro-adipogenic progenitors (FAPs) are tissue-resident mesenchymal stromal cells (MSCs) required for proper skeletal muscle development, regeneration and maintenance. However, FAPs are also responsible for fibro-fatty scar deposition following chronic damage. We aimed to investigate the role of functional cross-talk between TGF-β and PDGFRα signaling pathways in the fate of FAPs. Here, we show that the number of FAPs correlates with TGF-β levels and with extracellular matrix deposition during regeneration and repair. Interestingly, the expression of PDGFRα changed dynamically in the fibroblast lineage after injury. Furthermore, PDGFRα-dependent immediate early gene expression changed during regeneration and repair. We also found that TGF-β signaling reduces PDGFRα expression in FAPs, mouse dermal fibroblasts and in two related mesenchymal cell lines. Moreover, TGF-β promotes myofibroblast differentiation of FAPs but inhibits their adipogenicity. Accordingly, TGF-β impairs the expression of PDGFRα-dependent immediate early genes in a TGFBR1-dependent manner. Finally, pharmacological inhibition of PDGFRα activity with AG1296 impaired TGF-β-induced extracellular matrix remodeling, Smad2 signaling, myofibroblast differentiation and migration of MSCs. Thus, our work establishes a functional cross-talk between TGF-β and PDGFRα signaling pathways that is involved in regulating the biology of FAPs and/or MSCs.This article has an associated First Person interview with the first author of the paper.
纤维脂肪祖细胞（FAPs）是组织驻留的间充质基质细胞（MSCs），对于正常的骨骼肌发育、再生和维持是必需的。然而，FAPs 也是慢性损伤后纤维脂肪性瘢痕沉积的原因。我们旨在研究 TGF-β 和 PDGFRα 信号通路之间功能交叉对话在 FAP 命运中的作用。在这里，我们显示 FAPs 的数量与 TGF-β 水平以及再生和修复过程中的细胞外基质沉积相关。有趣的是，PDGFRα在损伤后成纤维细胞谱系中的表达动态变化。此外，PDGFRα依赖性即时早期基因表达在再生和修复过程中发生变化。我们还发现 TGF-β 信号在 FAPs、小鼠真皮成纤维细胞和两种相关间充质细胞系中降低 PDGFRα 的表达。此外，TGF-β 促进 FAPs 的肌成纤维细胞分化，但抑制其脂肪生成能力。因此，TGF-β 以 TGFBR1 依赖的方式损害 PDGFRα 依赖性即时早期基因的表达。最后，用 AG1296 抑制 PDGFRα 活性会损害 TGF-β 诱导的细胞外基质重塑、Smad2 信号、成肌纤维细胞分化和 MSC 迁移。因此，我们的工作确立了 TGF-β 和 PDGFRα 信号通路之间的功能交叉对话，该对话参与调节 FAPs 和/或 MSC 的生物学。本文有该论文第一作者的相关第一人称采访。
