Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA.
Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA.
Nat Commun. 2021 Dec 10;12(1):7179. doi: 10.1038/s41467-021-27499-8.
During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate excess myofibroblasts and extracellular matrix; herein, we focus on signaling in the mesenchyme. Our studies indicate that platelet-derived growth factor receptor (PDGFR)-β cells are the predominant source of myofibroblasts and Kruppel-like factor (KLF) 4 is upregulated in PDGFR-β cells, inducing TGFβ pathway signaling and fibrosis. In fibrotic lung patches, KLF4 is down-regulated, suggesting KLF4 levels decrease as PDGFR-β cells transition into myofibroblasts. In contrast to PDGFR-β cells, KLF4 reduction in α-smooth muscle actin (SMA) cells non-cell autonomously exacerbates lung fibrosis by inducing macrophage accumulation and pro-fibrotic effects of PDGFR-β cells via a Forkhead box M1 to C-C chemokine ligand 2-receptor 2 pathway. Taken together, in the context of lung fibrosis, our results indicate that KLF4 plays opposing roles in PDGFR-β cells and SMA cells and highlight the importance of further studies of interactions between distinct mesenchymal cell types.
在肺纤维化过程中，上皮细胞向下方的间质发出信号，导致肌成纤维细胞和细胞外基质过度生成；在此，我们重点关注间质中的信号转导。我们的研究表明，血小板衍生生长因子受体 (PDGFR)-β 细胞是肌成纤维细胞的主要来源，Krüppel 样因子 (KLF) 4 在 PDGFR-β 细胞中上调，诱导 TGFβ 通路信号转导和纤维化。在纤维化的肺斑块中，KLF4 下调，提示 KLF4 水平随着 PDGFR-β 细胞向肌成纤维细胞转化而降低。与 PDGFR-β 细胞不同，α-平滑肌肌动蛋白 (SMA) 细胞中 KLF4 的减少通过叉头框 M1 到 C-C 趋化因子配体 2 受体 2 通路非细胞自主地加剧肺纤维化，诱导巨噬细胞积累和促进 PDGFR-β 细胞的成纤维作用。总之，在肺纤维化的背景下，我们的研究结果表明，KLF4 在 PDGFR-β 细胞和 SMA 细胞中发挥相反的作用，并强调了进一步研究不同间充质细胞类型之间相互作用的重要性。
