ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts
ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts
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DOI：
10.1038/s41590-022-01285-0
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发表时间：
2022-08
影响因子：
30.5
通讯作者：
Minglu Yan;N. Komatsu;Ryunosuke Muro;N. Huynh;Yoshihiko Tomofuji;Y. Okada;Hiroshi I. Suzuki;Hiroyuki Takaba;R. Kitazawa;S. Kitazawa;W. Pluemsakunthai;Y. Mitsui;T. Satoh;T. Okamura;T. Nitta;S. Im;C. Kim;G. Kollias;Sakae Tanaka;Kazuo Okamoto;Masayuki Tsukasaki;H. Takayanagi
中科院分区：
文献类型：
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作者：
Minglu Yan;N. Komatsu;Ryunosuke Muro;N. Huynh;Yoshihiko Tomofuji;Y. Okada;Hiroshi I. Suzuki;Hiroyuki Takaba;R. Kitazawa;S. Kitazawa;W. Pluemsakunthai;Y. Mitsui;T. Satoh;T. Okamura;T. Nitta;S. Im;C. Kim;G. Kollias;Sakae Tanaka;Kazuo Okamoto;Masayuki Tsukasaki;H. Takayanagi
成纤维细胞，最丰富的结构细胞，发挥稳态功能，但也驱动疾病的发病机制。单细胞技术已经阐明了多种疾病中致病成纤维细胞的共同特征，包括自身免疫性关节炎，癌症和炎症性结肠炎。然而，疾病相关的成纤维细胞表型的分子机制仍不清楚。在这里，我们确定ETS 1作为关键的转录因子，在成纤维细胞的病理组织重塑程序。在关节炎中，ETS 1通过协调迄今未描述的破骨细胞分化因子受体核因子-κB配体激活因子（RANKL）以及基质金属蛋白酶的调节元件，驱动向组织破坏性成纤维细胞的极化。成纤维细胞特异性ETS 1缺失导致关节炎条件下骨和软骨损伤的改善，而不影响炎症水平。跨组织成纤维细胞单细胞数据分析和遗传功能丧失实验支持ETS 1定义了各种疾病环境中共享的扰动特异性成纤维细胞的概念。这些发现为致病性成纤维细胞极化提供了机制基础，并具有重要的治疗意义。
Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases including autoimmune arthritis, cancer and inflammatory colitis. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Here, we identify ETS1 as the key transcription factor governing the pathological tissue-remodeling programs in fibroblasts. In arthritis, ETS1 drives polarization toward tissue-destructive fibroblasts by orchestrating hitherto undescribed regulatory elements of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL) as well as matrix metalloproteinases. Fibroblast-specific ETS1 deletion resulted in ameliorated bone and cartilage damage under arthritic conditions without affecting the inflammation level. Cross-tissue fibroblast single-cell data analyses and genetic loss-of-function experiments lent support to the notion that ETS1 defines the perturbation-specific fibroblasts shared among various disease settings. These findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications.