Evidence map›Paper›PMID 42089296›Full record

ArticleAmerican journal of respiratory cell and molecular biology2026

Novel netrin-1-Unc5b-Klf4 axis balances AT2 survival in experimental bronchopulmonary dysplasia.

Oleksiy Klymenko, Jasmine Mohr, Soula Danopoulos, Ivana Mižík, Celien Kuiper-Makris, Stephanie Stephan, Mohammad A Mahjoub, Cristina M Alvira, Daniela Rheindorf, Thomas Imhof and 22 more

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Article in American journal of respiratory cell and molecular biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Glycyrrhizin alleviatesJournal of thoracic disease · 2026
    Article
4 · The record

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5 · Who and what money

Authors and funding

32 authors.

Oleksiy KlymenkoInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.
Jasmine MohrDepartment of Pediatric and Adolescent Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Cologne, Germany.
Soula DanopoulosThe Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, United States.
Ivana MižíkInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.
Celien Kuiper-MakrisDepartment of Pediatric and Adolescent Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Cologne, Germany.
Stephanie StephanInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.
Mohammad A MahjoubInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.
Cristina M AlviraDepartment of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA, United States.
Daniela RheindorfDepartment of Pediatric and Adolescent Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Cologne, Germany.
Thomas ImhofFaculty of Medicine, University of Cologne, and Center for Biochemistry and Institute for Dental Research and Oral Musculoskeletal Biology, University Hospital Cologne, Cologne, Germany.
Serife AkgülFaculty of Medicine, University of Cologne, and Center for Biochemistry and Institute for Dental Research and Oral Musculoskeletal Biology, University Hospital Cologne, Cologne, Germany.
Michele DonatoBiomedical Informatics Research, Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA, United States.
Lena K EbertCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Stefan MüllerCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Christina VohlenDepartment of Pediatric and Adolescent Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics, Cologne, Germany.
Dharmesh HiraniInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.
Christoph BartenhagenFaculty of Medicine, University of Cologne, and Center for Molecular Medicine Cologne, University Hospital Cologne, Cologne, Germany.
Marek BartkuhnInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.ORCID 0000-0001-6872-9082
Tara ProcidaInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.
Bernhard SchermerFaculty of Medicine, University of Cologne, and Center for Molecular Medicine Cologne, University Hospital Cologne, Cologne, Germany.
Purvesh KhatriBiomedical Informatics Research, Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA, United States.
Saverio BellusciDepartment of Internal Medicine II, Universities of Giessen and Marburg Lung Center, Cardiopulmonary Institute, Giessen, Germany.ORCID 0000-0002-9699-5262
Kerstin GothDepartment of Internal Medicine II, Universities of Giessen and Marburg Lung Center, Cardiopulmonary Institute, Giessen, Germany.
Ioannis AlexopoulosInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.
Theodoros GeorgomanolisFaculty of Medicine, University of Cologne, and University Hospital Cologne, Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Gloria S PryhuberDivision of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY,United States.
Soni S PullamsettiInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.
Werner SeegerInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.
Denise Al AlamThe Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, United States.
Jörg DötschDepartment of Pediatric and Adolescent Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.ORCID 0000-0003-1529-7647
Manuel KochFaculty of Medicine, University of Cologne, and Center for Molecular Medicine Cologne, University Hospital Cologne, Cologne, Germany.ORCID 0000-0002-2962-7814
Miguel A Alejandre AlcazarInstitute for Lung Health, Universities of Giessen and Marburg Lung Center, and Cardiopulmonary Institute, Member of the German Center for Lung Research.

Funding

Molecular Atlas of Lung Development - Data Coordinating CenterU01HL122638 · NHLBI · DUKE UNIVERSITY · PI CLARK, ROBERT F, PALMER, SCOTT M · 2014 to 2018
$7.5M
Biorepository for Investigation of Neonatal Diseases of Lung-Normal (BRINDL-NL)U01HL122700 · NHLBI · UNIVERSITY OF ROCHESTER · PI PRYHUBER, GLORIA S · 2014 to 2018
$6.1M
Type I IFN signaling during lung development in Down Syndrome-Multiome sequencing of human fetal and pediatric trisomy 21 lungsR01HL155104 · NHLBI · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · PI DANOPOULOS, SOULA ATHANASIA · 2021 to 2025
$3.3M
Developmental Heterogeneity of Pulmonary Endothelial Phenotype at Single Cell ResolutionR01HL154002 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ALVIRA, CRISTINA MARIA · 2021 to 2024
$2.8M
Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung VasculatureR01HL155828 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ALVIRA, CRISTINA MARIA · 2021 to 2024
$2.6M
Pericytes and postnatal alveolarization: Role of hypoxia inducible factorsR01HL160018 · NHLBI · STANFORD UNIVERSITY · PI ALVIRA, CRISTINA MARIA, CORNFIELD, DAVID N. · 2022 to 2025
$2.6M
Mechanisms controlling early human lung developmentR01HL141856 · NHLBI · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · PI AL-ALAM, DENISE · 2018 to 2022
$2.5M
Cardiopulmonary Institute 82 DZL C55B1Center for Molecular Medicine CologneData Coordinating Center 1U01HL122638Deutsche Forschungsgemeinschaft 1636/2-1Deutsche Forschungsgemeinschaft 1636/5-1German Center of Lung Research 82 DZL005C1German Center of Lung Research 82 DZLS85C1Institute for Lung Health 82 DZL 005C4LungMAP Research Center Biorepository 1U01HL122700Marga und Walter Boll Stiftung 210-01.03-21Marga und Walter Boll Stiftung 210-07.03-25Marga und Walter Boll Stiftung 210-09.01-18NHLBI NIH HHS R01 HL141856NHLBI NIH HHS R01HL141856NHLBI NIH HHS R01 HL154002NHLBI NIH HHS R01 HL155104NHLBI NIH HHS R01 HL155828NHLBI NIH HHS R01 HL160018NHLBI NIH HHS U01 HL122638NHLBI NIH HHS U01 HL122700NIHNIH HHS R01HL155104
6 · The paper itself

Abstract

Alveolar growth and repair are central processes in development and chronic lung disease, such as bronchopulmonary dysplasia (BPD), a neonatal lung disease without curative therapy. Alveolar epithelial type 2 (AT2) cells are the endogenous progenitor pool giving rise to alveolar epithelial type 1 cells and promoting alveolar repair. Since netrin-1, a regulator of cell homeostasis and stemness, has been linked to lung diseases, we now investigated its signaling and function in AT2 cells in a hyperoxia-based model of BPD and in lungs of infants with BPD. First, we demonstrated that prolonged hyperoxia reduced both netrin-1 and its receptor Unc5b in neonatal mouse lungs and in primary AT2 cells. Second, ex vivo studies using precision-cut lung slices (PCLS) and primary murine AT2 cell culture showed that netrin-1 regulates AT2 cell survival and the expression of Krüppel-like factor 4 (Klf4) through Unc5b, a transcription factor regulating cell survival. Third, single-cell and bulk transcriptomic analysis, as well as proximity-dependent biotin identification assay, showed Klf4 to be upregulated in AT2 cells during alveolarization, downstream of netrin-1, and to regulate AT2 cell survival. In vivo, Klf4 gene expression and protein abundance was significantly reduced in total lung homogenates and in AT2 cells of neonatal mice exposed to hyperoxia. Finally, KLF4+ cells, KLF4+ epithelial, and specifically KLF4+ AT2 cells were reduced in clinical BPD. In summary, our data identify a novel netrin-1-Unc5b-Klf4 axis in AT2 cells that is disrupted in BPD and could offer a novel target for endogenous alveolar repair.

Indexed as

Alveolar Epithelial CellsBronchopulmonary DysplasiaKruppel-Like Transcription FactorsNetrin-1Netrin ReceptorsAnimalsAnimals, NewbornCell SurvivalDisease Models, AnimalHumansHyperoxiaInfant, NewbornKruppel-Like Factor 4LungMiceMice, Inbred C57BLKLF4 protein, humanKlf4 protein, mouseKruppel-Like Factor 4Kruppel-Like Transcription FactorsNetrin-1Netrin ReceptorsNtn1 protein, mouseUnc5b protein, mousealveolar progenitors AT2bronchopulmonary dysplasiaKlf4lung regenerationNetrin-1 signaling

Identifiers

PMID42089296
PMCPMC13519333

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.