Single-cell RNA sequencing identifies G-protein coupled receptor 87 as a basal cell marker expressed in distal honeycomb cysts in idiopathic pulmonary fibrosis

Heinzelmann, Katharina; Hu, Qianjiang; Hu, Yan; Dobrinskikh, Evgenia; Ansari, Meshal; Melo-Narváez, M. Camila; Ulke, H.M.; Leavitt, Colton; Mirita, Carol; Trudeau, Tammy; Saal, Maxwell L.; Rice, Pamela L.; Gao, Bifeng; Janssen, William J.; Yang, Ivana V.; Schiller, Herbert B.; Vladar, Eszter K.; Lehmann, Mareike; Königshoff, Mélanie

doi:10.1183/13993003.02373-2021

Cited by 26 publications

(13 citation statements)

References 20 publications

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“…Moreover, although we have focused on FB in lung epithelial cells, other complement components have also been shown to modulate lung epithelial cell responses. For example, airway epithelial cells and alveolar (type 1 and type 2) epithelial cells also express C3aR, C5, C5aR1, and C5aR2, in addition to C3 and FB ( 22 , 56 , 57 ). C3aR activation on alveolar type 2 epithelial cells has recently been implicated in promoting endoplasmic reticulum stress and exacerbating bleomycin-induced lung injury, cellular apoptosis, and inflammation, which was suppressed by decay-accelerating factor (CD55) induction, a membrane-associated complement regulator ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

et al. 2023

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The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa . Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.

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Section: Discussionmentioning

confidence: 99%

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

et al. 2023

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“…Although the cellular complexity and spatial heterogeneity of disease in the lung presents fundamental challenges when using bulk-tissue methods for genomic analysis, single-cell biology approaches are well-suited for such investigations. Large collaborative studies using droplet-based single-cell RNA-sequencing (scRNA-seq) have refined understanding of the cellular makeup of the normal human lung [12][13][14][15] , and a number of studies have highlighted the dramatic changes in the cellular makeup and molecular programs in IPF lungs including a variety of disease-emergent and disease-perturbed cell types and states 10,[16][17][18][19][20][21][22] . Striking findings have included initial descriptions of a diversity of fibroblast subtypes 10,19,22 , accumulation of epithelial cells in the distal lung co-expressing molecular programs characteristic of AT2 cells and distal airway secretory cells 19 , emergence of KRT17+/KRT5-"aberrant basaloid" cells 19,20 , expansion of COL15A1+ endothelial cells 20 , and changes in macrophage phenotypes including prominent emergence of SPP1+ macrophages 17,18,23,24 .…”

Section: Mainmentioning

confidence: 99%

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

Vannan,

Lyu,

Williams

et al. 2023

Preprint

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The human lung is structurally complex, with a diversity of specialized epithelial, stromal and immune cells playing specific functional roles in anatomically distinct locations, and large-scale changes in the structure and cellular makeup of this distal lung is a hallmark of pulmonary fibrosis (PF) and other progressive chronic lung diseases. Single-cell transcriptomic studies have revealed numerous disease-emergent/enriched cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using sub-cellular resolution image-based spatial transcriptomics, we analyzed the gene expression of more than 1 million cells from 19 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell-types, established the cellular and molecular basis of classical PF histopathologic disease features, and identified a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Using machine-learning and trajectory analysis methods to segment and rank airspaces on a gradient from normal to most severely remodeled, we identified a sequence of compositional and molecular changes that associate with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially-resolved characterization of the cellular and molecular programs of PF and control lungs, provide new insights into the heterogeneous pathobiology of PF, and establish analytical approaches which should be broadly applicable to other imaging-based spatial transcriptomic studies.

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“…Besides, the contributions of diverse cell populations in the lung to pulmonary fibrosis pathogenesis are poorly understood. Recently, as an innovative technology, single-cell RNA sequencing (scRNA-seq) has been adopted to investigate the transcriptome heterogeneity of different cell types in many diseases (147), also including IPF (20,145,(148)(149)(150)(151)(152)(153)(154)(155)(156)(157). Taking advantage of genomics technology, especially the advances of scRNA-seq in recent decades, relevant studies could be designed to confirm the role of the PD-1/PD-L1 axis in IPF, identify the involved cell populations, and clarify the underlying regulatory mechanisms.…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

et al. 2022

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Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with a bleak prognosis. Mounting evidence suggests that IPF shares bio-molecular similarities with lung cancer. Given the deep understanding of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in cancer immunity and the successful application of immune checkpoint inhibitors (ICIs) in lung cancer, recent studies have noticed the role of the PD-1/PD-L1 axis in IPF. However, the conclusions are ambiguous, and the latent mechanisms remain unclear. In this review, we will summarize the role of the PD-1/PD-L1 axis in IPF based on current murine models and clinical studies. We found that the PD-1/PD-L1 pathway plays a more predominant profibrotic role than its immunomodulatory role in IPF by interacting with multiple cell types and pathways. Most preclinical studies also indicated that blockade of the PD-1/PD-L1 pathway could attenuate the severity of pulmonary fibrosis in mice models. This review will bring significant insights into understanding the role of the PD-1/PD-L1 pathway in IPF and identifying new therapeutic targets.

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Single-cell RNA sequencing identifies G-protein coupled receptor 87 as a basal cell marker expressed in distal honeycomb cysts in idiopathic pulmonary fibrosis

Abstract: It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.

Cited by 26 publications

References 20 publications

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

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