Integrative analysis of cell state changes in lung fibrosis with peripheral protein biomarkers

Mayr, Christoph H.; Simon, Lukas M.; Leuschner, Gabriela; Ansari, Meshal; Schniering, Janine; Geyer, Philipp; Angelidis, Ilias; Strunz, Maximilian; Singh, Pawandeep; Kneidinger, Nikolaus; Reichenberger, Frank; Silbernagel, Edith; Böhm, Stephan; Adler, Heiko; Lindner, Michael; Maurer, Britta; Hilgendorff, Anne; Prasse, Antje; Behr, Jürgen; Mann, Matthias; Eickelberg, Oliver; Theis, Fabian J.; Schiller, Herbert B.

doi:10.15252/emmm.202012871

Cited by 73 publications

(82 citation statements)

References 85 publications

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“…The power of large-scale single-cell cross-dataset analysis has been demonstrated in several recent studies [9][10][11][12][13][14][15] . We previously performed the first single-cell meta-analysis of the respiratory system, aggregating expression data of three genes important for SARS-CoV-2 cell entry from 31 datasets, spanning over 200 individuals 11 .…”

Section: Introductionmentioning

confidence: 98%

An integrated cell atlas of the human lung in health and disease

Sikkema

Strobl

Zappia

et al. 2022

Preprint

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126

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Organ- and body-scale cell atlases have the potential to transform our understanding of human biology. To capture the variability present in the population, these atlases must include diverse demographics such as age and ethnicity from both healthy and diseased individuals. The growth in both size and number of single-cell datasets, combined with recent advances in computational techniques, for the first time makes it possible to generate such comprehensive large-scale atlases through integration of multiple datasets. Here, we present the integrated Human Lung Cell Atlas (HLCA) combining 46 datasets of the human respiratory system into a single atlas spanning over 2.2 million cells from 444 individuals across health and disease. The HLCA contains a consensus re-annotation of published and newly generated datasets, resolving under- or misannotation of 59% of cells in the original datasets. The HLCA enables recovery of rare cell types, provides consensus marker genes for each cell type, and uncovers gene modules associated with demographic covariates and anatomical location within the respiratory system. To facilitate the use of the HLCA as a reference for single-cell lung research and allow rapid analysis of new data, we provide an interactive web portal to project datasets onto the HLCA. Finally, we demonstrate the value of the HLCA reference for interpreting disease-associated changes. Thus, the HLCA outlines a roadmap for the development and use of organ-scale cell atlases within the Human Cell Atlas.

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Section: Introductionmentioning

confidence: 98%

An integrated cell atlas of the human lung in health and disease

Sikkema

Strobl

Zappia

et al. 2022

Preprint

Self Cite

126

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“…Subsequently, in order to further increase data resolution, we have pinpointed marker genes of all pathology-originating cells compared to healthy donated ones, as integrated by Mayr et al 13 . Pathology versus healthy state comparisons were performed for over 40 cell types’ top variable genes, resulting in an expression profiling of ten different pulmonary diseases.…”

Section: Resultsmentioning

confidence: 99%

“…Last, in order to combine the better established methods of bulk DEA with the higher resolution of single cell data, Gene explorer maps each requested gene to single cell datasets of NU-Pulmonary cell browser in a species specific manner: human to Reyfman 27 and murine to Joshi-Watanabe 28 and Xie 29 datasets. More details on published scRNA-seq pulmonary fibrosis datasets can be found in the Single cell data tab of our web server, along with DEA results of Mayr et al dataset 13 in a tabular format. Please, refer to "Single cell data" section of the paper for more details.…”

Section: Resultsmentioning

confidence: 99%

“…As mapping of genes at the single cell level through the Gene expression tab is limited to visual inspection of feature plots, we designed the Single cell data tab in order to provide detailed DEA statistical data from one of the biggest datasets regarding lung fibrosis 13 (233,638 cells from 10 pulmonary diseases and control donor samples). More specifically, through Search data sub-tab the user can access DEA data of the top 2000 most variable genes, examined for differentiating expression levels between each pathology and the control cells.…”

Section: Resultsmentioning

confidence: 99%

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Fibromine is a multi-omics database and mining tool for target discovery in pulmonary fibrosis

Fanidis

Moulos

Aidinis

2021

Sci Rep

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Idiopathic pulmonary fibrosis is a lethal lung fibroproliferative disease with limited therapeutic options. Differential expression profiling of affected sites has been instrumental for involved pathogenetic mechanisms dissection and therapeutic targets discovery. However, there have been limited efforts to comparatively analyse/mine the numerous related publicly available datasets, to fully exploit their potential on the validation/creation of novel research hypotheses. In this context and towards that goal, we present Fibromine, an integrated database and exploration environment comprising of consistently re-analysed, manually curated transcriptomic and proteomic pulmonary fibrosis datasets covering a wide range of experimental designs in both patients and animal models. Fibromine can be accessed via an R Shiny application (http://www.fibromine.com/Fibromine) which offers dynamic data exploration and real-time integration functionalities. Moreover, we introduce a novel benchmarking system based on transcriptomic datasets underlying characteristics, resulting to dataset accreditation aiming to aid the user on dataset selection. Cell specificity of gene expression can be visualised and/or explored in several scRNA-seq datasets, in an effort to link legacy data with this cutting-edge methodology and paving the way to their integration. Several use case examples are presented, that, importantly, can be reproduced on-the-fly by a non-specialist user, the primary target and potential user of this endeavour.

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“…Kramann et al verified that perivascular Gli1+ MSC-like cells (i.e., pericytes) are one of the main sources of myofibroblasts in various organs by tracing their genetic lineage (Kramann et al, 2015). Based on that study, Mayr et al discovered a new pericyte state related to interstitial lung disease (ILD), namely, SSTR2+/CFHR1+ pericytes (somatostatin receptor two and complement factor H related 1) with high disease specificity, which have a proinflammatory phenotype and can express various chemokines (Mayr et al, 2021). It has been proven that pericytes separate from Ecs during chronic kidney injury and many studies have found that the separated pericytes show a tendency to differentiate into myofibroblasts (Bábíčková et al, 2017;Liu et al, 2018;Yamaguchi et al, 2020).…”

Section: Pericytesmentioning

confidence: 99%

The Impact of Inflammatory Immune Reactions of the Vascular Niche on Organ Fibrosis

et al. 2021

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Inflammation is a type of defense response against tissue damage, and can be mediated by lymphocytes and macrophages. Fibrosis is induced by tissue injury and inflammation, which leads to an increase in fibrous connective tissue in organs and a decrease in organ parenchyma cells, finally leading to organ dysfunction or even failure. The vascular niche is composed of endothelial cells, pericytes, macrophages, and hematopoietic stem cells. It forms a guiding microenvironment for the behavior of adjacent cells, and mainly exists in the microcirculation, including capillaries. When an organ is damaged, the vascular niche regulates inflammation and affects the repair of organ damage in a variety of ways, such as via its angiocrine function and transformation of myofibroblasts. In this paper, the main roles of vascular niche in the process of organ fibrosis and its mechanism of promoting the progress of fibrosis through inflammatory immunoregulation are summarized. It was proposed that the vascular niche should be regarded as a new therapeutic target for organ fibrosis, suggesting that antifibrotic effects could be achieved by regulating macrophages, inhibiting endothelial-mesenchymal transition, interfering with the angiocrine function of endothelial cells, and inhibiting the transformation of pericytes into myofibroblasts, thus providing new ideas for antifibrosis drug research.

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Integrative analysis of cell state changes in lung fibrosis with peripheral protein biomarkers

Cited by 73 publications

References 85 publications

An integrated cell atlas of the human lung in health and disease

An integrated cell atlas of the human lung in health and disease

Fibromine is a multi-omics database and mining tool for target discovery in pulmonary fibrosis

The Impact of Inflammatory Immune Reactions of the Vascular Niche on Organ Fibrosis

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