Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage

Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage

2019 February ; 20(2): 163–172. doi:10.1038/s41590-018-0276-y. | Dvir Aran#1, Agnieszka P. Looney#2, Leqian Liu#3, Esther Wu2, Valerie Fong2, Austin Hsu4, Suzanna Chak2, Ram P. Naikawadi2, Paul J. Wolters2, Adam R. Abate3,5,6, Atul J. Butte1, and Mallar Bhattacharya2,*
This study investigates the role of macrophages in lung fibrosis using single-cell RNA sequencing (scRNA-seq) and a novel computational framework called SingleR. SingleR enhances the annotation of scRNA-seq data by comparing single-cell transcriptomes to reference datasets. The analysis reveals a novel subgroup of CX3CR1+SiglecF+ transitional macrophages that are intermediate between monocyte-derived and alveolar macrophages. These transitional macrophages are localized to the fibrotic niche and exhibit a profibrotic effect in vivo. The expression of genes associated with these transitional macrophages is upregulated in samples from patients with idiopathic pulmonary fibrosis. Mechanistically, these macrophages secrete PDGF-aa, which promotes fibroblast proliferation. Deletion of these macrophages during the fibrotic phase prevents lung fibrosis, highlighting their critical role in the fibrotic response to injury. The findings provide new insights into the heterogeneity of macrophages and their functional roles in fibrosis, suggesting potential therapeutic targets.This study investigates the role of macrophages in lung fibrosis using single-cell RNA sequencing (scRNA-seq) and a novel computational framework called SingleR. SingleR enhances the annotation of scRNA-seq data by comparing single-cell transcriptomes to reference datasets. The analysis reveals a novel subgroup of CX3CR1+SiglecF+ transitional macrophages that are intermediate between monocyte-derived and alveolar macrophages. These transitional macrophages are localized to the fibrotic niche and exhibit a profibrotic effect in vivo. The expression of genes associated with these transitional macrophages is upregulated in samples from patients with idiopathic pulmonary fibrosis. Mechanistically, these macrophages secrete PDGF-aa, which promotes fibroblast proliferation. Deletion of these macrophages during the fibrotic phase prevents lung fibrosis, highlighting their critical role in the fibrotic response to injury. The findings provide new insights into the heterogeneity of macrophages and their functional roles in fibrosis, suggesting potential therapeutic targets.
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