Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis
Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis
复制标题
meflin阳性成纤维细胞在肺纤维化中具有抗纤维化特性
DOI：
10.1183/13993003.03397-2020
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发表时间：
2021-12-01
影响因子：
24.3
通讯作者：
Hasegawa, Yoshinori
中科院分区：
文献类型：
--
作者：
Nakahara, Yoshio;Hashimoto, Naozumi;Hasegawa, Yoshinori
老年特发性肺纤维化（IPF）患者的预后仍然很差。成纤维细胞病灶（其中涉及增殖成纤维细胞和肌成纤维细胞的聚集体）是IPF的病理学标志性病变，代表活跃纤维形成的局灶性区域。纤维化病变中成纤维细胞的异质性阻碍了肺纤维化发病机制的发现。因此，为了确定IPF的发病机制，需要鉴定功能性成纤维细胞。本研究的目的是确定meflin阳性的成纤维细胞的作用，确定为间充质基质细胞的潜在标志物，在肺纤维化的发展过程中，我们通过单细胞RNA测序（scRNA-seq）建立的单细胞图谱中的meflin阳性细胞的特征分析243472细胞从32个IPF肺和29个正常肺样本。我们确定了使用博莱霉素（BLM）诱导的肺纤维化的成纤维细胞阳性的作用。scRNA-seq结合原位RNA杂交鉴定了IPF患者纤维化肺的成纤维细胞病灶中对甲氨蝶呤呈阳性的增殖成纤维细胞，而不是致密纤维化。BLM诱导的meflin缺陷小鼠的肺纤维化模型显示，meflin阳性的成纤维细胞具有抗纤维化特性，以防止肺纤维化。虽然转化生长因子-β诱导的纤维化和细胞衰老与衰老相关的分泌表型在成纤维细胞中通过抑制或缺乏meflin而加剧，但这些在meflin缺乏的成纤维细胞中被抑制与meflin重建。这些发现提供了证据，以显示在肺纤维化的活动性纤维化区域中的成纤维细胞和肌成纤维细胞上的meflin表达的生物学重要性。
The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine the pathogenesis of IPF, identification of functional fibroblasts is warranted. The aim of this study was to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis.We characterised meflin-positive cells in a single-cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243472 cells from 32 IPF lungs and 29 normal lung samples. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic properties to prevent pulmonary fibrosis. Although transforming growth factor-beta-induced fibrogenesis and cell senescence with the senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.