肌成纤维细胞
成纤维细胞
间质性肺病
间充质干细胞
纤维化
特发性肺纤维化
肺纤维化
转录组
人口
医学
表型
细胞外基质
病理
癌症研究
生物
肺
内科学
细胞生物学
基因表达
基因
细胞培养
遗传学
环境卫生
作者
Eleanor Valenzi,Melissa Bulik,Tracy Tabib,Christina Morse,John Sembrat,Humberto E. Trejo Bittar,Mauricio Rojas,Robert Lafyatis
标识
DOI:10.1136/annrheumdis-2018-214865
摘要
Objectives Myofibroblasts are key effector cells in the extracellular matrix remodelling of systemic sclerosis-associated interstitial lung disease (SSc-ILD); however, the diversity of fibroblast populations present in the healthy and SSc-ILD lung is unknown and has prevented the specific study of the myofibroblast transcriptome. We sought to identify and define the transcriptomes of myofibroblasts and other mesenchymal cell populations in human healthy and SSc-ILD lungs to understand how alterations in fibroblast phenotypes lead to SSc-ILD fibrosis. Methods We performed droplet-based, single-cell RNA-sequencing with integrated canonical correlation analysis of 13 explanted lung tissue specimens (56 196 cells) from four healthy control and four patients with SSc-ILD, with findings confirmed by cellular indexing of transcriptomes and epitopes by sequencing in additional samples. Results Examination of gene expression in mesenchymal cells identified two major, SPINT2 hi and MFAP5 hi , and one minor, WIF1 hi , fibroblast populations in the healthy control lung. Combined analysis of control and SSc-ILD mesenchymal cells identified SPINT2 hi , MFAP5 hi , few WIF1 hi fibroblasts and a new large myofibroblast population with evidence of actively proliferating myofibroblasts. We compared differential gene expression between all SSc-ILD and control mesenchymal cell populations, as well as among the fibroblast subpopulations, showing that myofibroblasts undergo the greatest phenotypic changes in SSc-ILD and strongly upregulate expression of collagens and other profibrotic genes. Conclusions Our results demonstrate previously unrecognised fibroblast heterogeneity in SSc-ILD and healthy lungs, and define multimodal transcriptome-phenotypes associated with these populations. Our data indicate that myofibroblast differentiation and proliferation are key pathological mechanisms driving fibrosis in SSc-ILD.
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