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- Sikkema, Lisa, et al.
(författare)
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An integrated cell atlas of the lung in health and disease
- 2023
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Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
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| 2. |
- Wagner, Darcy, et al.
(författare)
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LSC - 2017 - Hippo-YAP/TAZ signaling is deranged in IPF
- 2017
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Ingår i: European Respiratory Journal. - 0903-1936. ; 50:Suppl. 61
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Konferensbidrag (refereegranskat)abstract
- Objective: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no cure and is characterized by deranged epithelial repair, myofibroblast activation, and excess deposition of extracellular matrix. Yes associated protein (YAP) and transcriptional co-regulator with PDZ-binding domain(TAZ), co-transcriptional activators of the Hippo pathway and proto-oncogenes, were recently found to be deranged in IPF. The cause of their dysregulation remain unknown. Hippo signaling regulates several endogenous progenitor cell functions through YAP/TAZ. We hypothesized that Hippo signaling is downregulated in IPF, resulting in increased YAP/TAZ activity.Methods and Results: We assessed normal and fibrotic (IPF or intratracheal bleomycin-treated murine) lung tissue using immunohistochemistry, qPCR, and Gene Set Enrichment Analysis to identify cell types with deranged YAP/TAZ. Distal epithelial cells and fibroblasts were found to have dysregulated YAP/TAZ activity. Hippo components were downregulated in IPF and fibrotic mice, including in murine alveolar type II cells (mATII). Secretion of YAP/TAZ targets with pro-fibrotic activity was increased in fibrotic mATII as detected by mass spectrometry proteomics. Principal component analysis using Hippo expression in the Lung Gene Research Consortium separated IPF from normal patients. Fibrotic markers, including YAP/TAZ targets and myofibroblast activation, were reduced in the bleomycin model of fibrosis and in a novel ex vivo model of early pulmonary fibrosis in human precision cut lung slices when verteporfin, an FDA approved drug and YAP/TAZ inhibitor, was used therapeutically.Conclusion: Hippo-YAP/TAZ are deranged in IPF. Pharmaceutical targeting of YAP/TAZ and or restoration of Hippo signaling may represent a new therapeutic strategy for IPF.
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