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The Progenitor Cell Marker LGR5 Is Reduced in Epithelial Cells in Emphysema
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A3827 - The Progenitor Cell Marker LGR5 Is Reduced in Epithelial Cells in Emphysema
Author Block: Y. Hu1, W. A. Skronska-Wasek2, C. Ota2, K. I. Mutze2, H. Baarsma2, D. E. Wagner2, M. Lehmann2, K. R. Bracke3, G. G. Brusselle3, A. O. Yildirim2, M. Koenigshoff1; 1Department of Medicine, Division of Pulmonary Science and Critical Care, University of Colorado Anschutz Medical Campus, Denver, Aurora, CO, United States, 2Comprehensive Pneumology Center, Ludwig Maximilian University, University Hospital Grosshadern, and Helmholtz Zentrum München, Munich, Germany, 3Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
RATIONALE
The progenitor marker, leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) exhibits a capacity to enhance WNT/β-catenin signaling, which has been shown to be down-regulated in chronic obstructive pulmonary disease (COPD)/emphysema, particularly in alveolar epithelial type II (ATII) cells. However, the role of LGR5 in COPD/emphysema remains unknown.
HYPOTHESIS
Dysregulated LGR5 expression contributes to reduced WNT/β-catenin signaling in the emphysematous lung.
METHODS
Flow cytometry, quantitative PCR (qPCR), microarray, western, immunofluorescence, animal model of emphysema with cigarette smoke (CS) treatment, primary mouse ATII (pmATII) cell isolation and culture with cigarette smoke extract (CSE) and H2O2 treatment and TOP/FOP flash assay.
RESULTS
First, we identified a small population (3.44%) of LGR5+EpCAM+ cells in the single cell suspension of mouse lung by flow cytometry. Using qPCR, western blotting and immunofluorescence, we found that Lgr5 expression is enriched in ATII cells and decreased during ATII-ATI trans-differentiation. Strikingly, in the murine CS-induced emphysema model in vivo and pmATII cell cultures in vitro treated with CSE and H2O2 to induce senescence, LGR5 was directly reduced. Moreover, we found significantly decreased LGR5 in the lung tissue of COPD patients and smokers using microarray analysis. Lastly, in cultured pmATII cells, the potential ligand of LGR5, R-Spondin (RSPO)2, induced expression of both Lgr5 and the Wnt target gene Axin2. Moreover, we showed that treatment of RSPO2 led to induction of canonical Wnt signaling in a TOP/FOP flash assay.
CONCLUSIONS
The expression of LGR5 in alveolar epithelial cells is reduced in COPD/emphysema, which might be responsible for the impaired WNT/β-catenin signaling and tissue repair during disease progression. The LGR5 ligand RSPO2 should be further investigated for its potential to induce lung repair.
Author Block: Y. Hu1, W. A. Skronska-Wasek2, C. Ota2, K. I. Mutze2, H. Baarsma2, D. E. Wagner2, M. Lehmann2, K. R. Bracke3, G. G. Brusselle3, A. O. Yildirim2, M. Koenigshoff1; 1Department of Medicine, Division of Pulmonary Science and Critical Care, University of Colorado Anschutz Medical Campus, Denver, Aurora, CO, United States, 2Comprehensive Pneumology Center, Ludwig Maximilian University, University Hospital Grosshadern, and Helmholtz Zentrum München, Munich, Germany, 3Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
RATIONALE
The progenitor marker, leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) exhibits a capacity to enhance WNT/β-catenin signaling, which has been shown to be down-regulated in chronic obstructive pulmonary disease (COPD)/emphysema, particularly in alveolar epithelial type II (ATII) cells. However, the role of LGR5 in COPD/emphysema remains unknown.
HYPOTHESIS
Dysregulated LGR5 expression contributes to reduced WNT/β-catenin signaling in the emphysematous lung.
METHODS
Flow cytometry, quantitative PCR (qPCR), microarray, western, immunofluorescence, animal model of emphysema with cigarette smoke (CS) treatment, primary mouse ATII (pmATII) cell isolation and culture with cigarette smoke extract (CSE) and H2O2 treatment and TOP/FOP flash assay.
RESULTS
First, we identified a small population (3.44%) of LGR5+EpCAM+ cells in the single cell suspension of mouse lung by flow cytometry. Using qPCR, western blotting and immunofluorescence, we found that Lgr5 expression is enriched in ATII cells and decreased during ATII-ATI trans-differentiation. Strikingly, in the murine CS-induced emphysema model in vivo and pmATII cell cultures in vitro treated with CSE and H2O2 to induce senescence, LGR5 was directly reduced. Moreover, we found significantly decreased LGR5 in the lung tissue of COPD patients and smokers using microarray analysis. Lastly, in cultured pmATII cells, the potential ligand of LGR5, R-Spondin (RSPO)2, induced expression of both Lgr5 and the Wnt target gene Axin2. Moreover, we showed that treatment of RSPO2 led to induction of canonical Wnt signaling in a TOP/FOP flash assay.
CONCLUSIONS
The expression of LGR5 in alveolar epithelial cells is reduced in COPD/emphysema, which might be responsible for the impaired WNT/β-catenin signaling and tissue repair during disease progression. The LGR5 ligand RSPO2 should be further investigated for its potential to induce lung repair.
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