BMP3b Is a Novel Antifibrotic Molecule Regulated by Meflin in Lung Fibroblasts
BMP3b Is a Novel Antifibrotic Molecule Regulated by Meflin in Lung Fibroblasts
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BMP3b 是肺成纤维细胞中受 Meflin 调节的新型抗纤维化分子
DOI：
10.1165/rcmb.2021-0484oc
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发表时间：
2022
影响因子：
6.4
通讯作者：
Hashimoto Naozumi
中科院分区：
文献类型：
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作者：
Suzuki Atsushi;Sakamoto Koji;Nakahara Yoshio;Enomoto Atsushi;Hino Jun;Ando Akira;Inoue Masahide;Shiraki Yukihiro;Omote Norihito;Kusaka Masahiro;Fukihara Jun;Hashimoto Naozumi
成纤维细胞在肺纤维化过程中起核心作用。我们最近的研究确定了一种新的肺成纤维细胞亚群表达meflin（间充质基质细胞和成纤维细胞表达Linx parklin），其抗纤维化特性已通过鼠肺纤维化模型证实。表达Meflin的成纤维细胞对TGF-β（转化生长因子-β）诱导的纤维化具有抗性，但其潜在机制尚不清楚。在这项研究中，二氧化硅纳米颗粒诱导的肺纤维化模型的评价证实了甲氨蝶呤通过调节TGF-β信号传导的抗纤维化作用。我们在肺成纤维细胞中进行了比较基因表达谱分析，确定了编码骨形态发生蛋白3b（BMP 3b）的生长分化因子10（Gdf 10）是TGF-β促纤维化条件下meflin缺陷细胞中下调最多的基因。我们假设BMP 3b可能是一种效应分子，在meflin下游发挥抗纤维化作用。如单细胞转录组学数据所示，证实了Gdf 10（Bmp 3b）在包括成纤维细胞在内的基质细胞中的限制性表达。我们检测了BMP 3b在肺成纤维细胞中可能的抗纤维化特性，并证明Bmp 3b缺失的成纤维细胞对TGF-β诱导的纤维化变化更敏感。此外，Bmp 3b基因敲除小鼠在体内表现出二氧化硅纳米颗粒诱导的过度肺纤维化。我们还证明了用重组BMP 3B治疗对成纤维细胞中TGF-β诱导的纤维化是有效的，特别是在抑制过度的细胞外基质产生方面。这些证据表明，BMP 3b是一种新的体液效应分子调节的meflin发挥抗纤维化的特性，在肺成纤维细胞。补充BMP 3B可能是纤维化肺疾病的一种新的治疗策略。
Fibroblasts play a central role in the lung fibrotic process. Our recent study identified a novel subpopulation of lung fibroblasts expressing meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), antifibrotic properties of which were confirmed by murine lung fibrosis model. Meflin-expressing fibroblasts were resistant to fibrogenesis induced by TGF-β (transforming growth factor-β), but its underlying mechanisms remain unknown. In this study, evaluation of a silica-nanoparticle–induced lung fibrosis model confirmed the antifibrotic effect of meflin via the regulation of TGF-β signaling. We conducted comparative gene expression profiling in lung fibroblasts, which identified growth differentiation factor 10 (Gdf10) encoding bone morphogenic protein 3b (BMP3b) as the most downregulated gene in meflin-deficient cells under the profibrotic condition with TGF-β. We hypothesized that BMP3b can be an effector molecule playing an antifibrotic role downstream of meflin. As suggested by single-cell transcriptomic data, restricted expressions ofGdf10 (Bmp3b)in stromal cells including fibroblasts were confirmed. We examined possible antifibrotic properties of BMP3b in lung fibroblasts and demonstrated thatBmp3b-null fibroblasts were more susceptible to TGF-β–induced fibrogenic changes. Furthermore,Bmp3b-null mice exhibited exaggerated lung fibrosis induced by silica-nanoparticlesin vivo. We also demonstrated that treatment with recombinant BMP3B was effective against TGF-β-induced fibrogenesis in fibroblasts, especially in the suppression of excessive extracellular matrix production. These lines of evidence suggested that BMP3b is a novel humoral effector molecule regulated by meflin which exerts antifibrotic properties in lung fibroblasts. Supplementation of BMP3B could be a novel therapeutic strategy for fibrotic lung diseases.