Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis.
Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis.
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DOI：
10.1186/s12931-023-02419-0
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发表时间：
2023-04-21
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
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作者：
特发性肺纤维化（IPF）是一种与年龄相关的进行性肺部疾病，其疤痕组织堆积会损害气体交换。先前的高通量研究阐明了细胞异质性和分子途径在晚期疾病中的作用。然而，成纤维细胞从正常向促纤维化转变过程中发生的关键致病途径在很大程度上被忽视了。我们使用来自健康对照和 IPF 患者（下叶和上叶）肺部的单细胞转录组学 (scRNA-seq)。我们确定了与早期疾病相关的成纤维细胞亚群、基因和途径。免疫荧光测定验证了 MOXD1 在纤维化早期的作用。我们确定了四个不同的成纤维细胞亚群，其中一个标记了正常向促纤维化状态的转变。我们的结果首次表明，核糖体蛋白的整体下调和大多数铜结合蛋白（包括 MOXD1）的显着上调标志着 IPF 的转变。我们发现 IPF 上叶和下叶样本中的基因表达没有显着差异，这些样本分别被选择为具有低纤维化程度和高度纤维化程度。成纤维细胞 IPF 发病期间的早期事件包括核糖体和铜结合蛋白的失调。早期 IPF 的成纤维细胞可能已经获得促纤维化表型，而晚期疾病的标志，包括成纤维细胞灶和蜂窝状形成，仍然不明显。我们发现的新的过渡成纤维细胞对于研究成纤维细胞可塑性在疾病进展中的作用非常重要，并有助于开发针对早期疾病状态的早期诊断工具和治疗干预措施。在线版本包含可在 10.1186/s12931-023-02419-0 获取的补充材料。
Idiopathic Pulmonary Fibrosis (IPF) is an age-associated progressive lung disease with accumulation of scar tissue impairing gas exchange. Previous high-throughput studies elucidated the role of cellular heterogeneity and molecular pathways in advanced disease. However, critical pathogenic pathways occurring in the transition of fibroblasts from normal to profibrotic have been largely overlooked. We used single cell transcriptomics (scRNA-seq) from lungs of healthy controls and IPF patients (lower and upper lobes). We identified fibroblast subclusters, genes and pathways associated with early disease. Immunofluorescence assays validated the role of MOXD1 early in fibrosis. We identified four distinct fibroblast subgroups, including one marking the normal-to-profibrotic state transition. Our results show for the first time that global downregulation of ribosomal proteins and significant upregulation of the majority of copper-binding proteins, including MOXD1, mark the IPF transition. We find no significant differences in gene expression in IPF upper and lower lobe samples, which were selected to have low and high degree of fibrosis, respectively. Early events during IPF onset in fibroblasts include dysregulation of ribosomal and copper-binding proteins. Fibroblasts in early stage IPF may have already acquired a profibrotic phenotype while hallmarks of advanced disease, including fibroblast foci and honeycomb formation, are still not evident. The new transitional fibroblasts we discover could prove very important for studying the role of fibroblast plasticity in disease progression and help develop early diagnosis tools and therapeutic interventions targeting earlier disease states. The online version contains supplementary material available at 10.1186/s12931-023-02419-0.
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影响因子：
4.6
作者：
Aumiller V;Strobel B;Romeike M;Schuler M;Stierstorfer BE;Kreuz S
通讯作者：
Kreuz S
影响因子：
--
作者：
Habiel DM;Hogaboam CM
通讯作者：
Hogaboam CM
影响因子：
5.6
作者：
Kendall RT;Feghali-Bostwick CA
通讯作者：
Feghali-Bostwick CA
影响因子：
64.8
作者：
La Manno G;Soldatov R;Zeisel A;Braun E;Hochgerner H;Petukhov V;Lidschreiber K;Kastriti ME;Lönnerberg P;Furlan A;Fan J;Borm LE;Liu Z;van Bruggen D;Guo J;He X;Barker R;Sundström E;Castelo-Branco G;Cramer P;Adameyko I;Linnarsson S;Kharchenko PV
通讯作者：
Kharchenko PV
影响因子：
7.3
作者：
Merkt W;Bueno M;Mora AL;Lagares D
通讯作者：
Lagares D