Fibroblast-derived osteoglycin promotes epithelial cell repair
There is an urgent need for innovative therapies targeting defective epithelial repair in chronic diseases like COPD. The mesenchymal niche is a critical regulator in epithelial stem cell activation, suggesting that their secreted factors are possible potent drug targets. Utilizing a proteomics-guided drug discovery strategy, we explored the lung fibroblast secretome to uncover impactful drug targets. Our lung organoid assays identified several regenerative ligands, with osteoglycin (OGN) showing the most profound effects. Transcriptomic analyses revealed that OGN enhances alveolar progenitor differentiation, detoxifies reactive oxygen species, and strengthens fibroblast-epithelial crosstalk. OGN expression was diminished in COPD patients and smoke-exposed mice. An active fragment of OGN (leucine-rich repeat regions 4-7) replicated full-length OGN's regenerative effects, significantly ameliorating elastase-induced lung injury in lung slices and improving lung function in vivo. These findings highlight OGN as a pivotal secreted protein for alveolar epithelial repair, positioning its active fragment as a promising therapeutic for COPD.
Authors
- Maunick Lefin Koloko Ngassie (ORCID: https://orcid.org/0000-0003-2899-3983)
- Henderik W. Frijlink (ORCID: https://orcid.org/0000-0001-7901-8198)
- Anika Nagelkerke (ORCID: https://orcid.org/0000-0002-7541-588X)
- Manon E. Woest
- Wim Timens (ORCID: https://orcid.org/0000-0002-4146-6363)
- Luke van der Koog (ORCID: https://orcid.org/0000-0001-6785-0921)
- Reinoud Gosens (ORCID: https://orcid.org/0000-0002-5595-152X)
- Önder Yildirim
- Justina C. Wolters (ORCID: https://orcid.org/0000-0003-0066-3720)
- Y. S. Prakash (ORCID: https://orcid.org/0000-0002-2968-224X)
- Annet B. Zuidhof
- Corry‐Anke Brandsma (ORCID: https://orcid.org/0000-0001-8911-3658)
- Péter Horvatovich (ORCID: https://orcid.org/0000-0003-2218-1140)
- Deepesh Dhakad
- Dyan F. Nugraha
- Sophie I T Bos
- Iris C. Gorter
- Robin A B Elferink
- Vicky Verschut
Institutions
- University Medical Center Groningen (NL)
- University of Groningen (NL)
- Dialyse Centrum Groningen (NL)
- Mayo Clinic in Arizona (US)
- German Center for Lung Research (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- npj Regenerative Medicine
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1038/s41536-025-00404-3
- Citations
- 4
- Primary Topic
- Neonatal Respiratory Health Research
- Type
- article
- Field-Weighted Citation Impact
- 6.07
Funders
- Rijksuniversiteit Groningen
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Stichting Astma Bestrijding