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Wu, X.* ; Bos, I.S.T.* ; Conlon, T.M. ; Ansari, M. ; Verschut, V.* ; van der Koog, L.* ; Verkleij, L.A.* ; D'Ambrosi, A.* ; Matveyenko, A.* ; Schiller, H. B. ; Königshoff, M.* ; Schmidt, M.* ; Kistemaker, L.E.M.* ; Yildirim, A.Ö. ; Gosens, R.*

A transcriptomics-guided drug target discovery strategy identifies receptor ligands for lung regeneration.

Sci. Adv. 8:eabj9949 (2022)

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Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here, we used a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors, of which we screened the function in lung organoids. We found several drug targets with regenerative potential, of which EP and IP prostanoid receptor ligands had the most profound therapeutic potential in restoring cigarette smoke-induced defects in alveolar epithelial progenitors in vitro and in vivo. Mechanistically, we found, using single-cell RNA sequencing analysis, that circadian clock and cell cycle/apoptosis signaling pathways were differentially expressed in alveolar epithelial progenitor cells in patients with COPD and in a relevant model of COPD, which was prevented by prostaglandin E2 or prostacyclin mimetics. We conclude that specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

ISSN (print) / ISBN 2375-2548

e-ISSN 2375-2548

Journal Science Advances

Quellenangaben Volume: 8, Issue: 12, Article Number: eabj9949

Publisher American Association for the Advancement of Science (AAAS)

Publishing Place Washington, DC [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Lung Health and Immunity (LHI)
German Center for Lung Research (DZL)

Grants Lung Foundation Netherlands
China Scholarship Council
University of Groningen