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

Xinhui Wu, I. Sophie, Thomas M. Conlon, Meshal Ansari, Vicky Verschut, Luke Van der Koog, Lars A. Verkleij, Angela D'Ambrosi, Aleksey Matveyenko, Herbert B. Schiller, Melanie Konigshoff, Martina Schmidt, Loes E.M. Kistemaker, Ali Onder Yildirim, Reinoud Gosens

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
JournalScience Advances
Issue number12
StatePublished - Mar 2022

ASJC Scopus subject areas

  • General


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