Advertisement

ResearchIn-Press PreviewGeneticsPulmonology Open Access | 10.1172/jci.insight.196651

Single-cell multi-omic analysis of mesenchymal cells reveals molecular signatures and regulators of lung allograft fibrosis

Lu Lu,1 A. Patrick McLinden,2 Natalie M. Walker,3 Ragini Vittal,2 Yichen Wang,1 Fatemeh Fattahi,3 Stephen T. Russell,2 Michael P. Combs,3 Joshua D. Welch,1 and Vibha N. Lama2

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by Lu, L. in: PubMed | Google Scholar

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by McLinden, A. in: PubMed | Google Scholar

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by Walker, N. in: PubMed | Google Scholar |

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by Vittal, R. in: PubMed | Google Scholar

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by Wang, Y. in: PubMed | Google Scholar

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by Fattahi, F. in: PubMed | Google Scholar

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by Russell, S. in: PubMed | Google Scholar

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by Combs, M. in: PubMed | Google Scholar |

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by Welch, J. in: PubMed | Google Scholar |

1Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States of America

2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, United States of America

3Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, United States of America

4Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Ann Arbor, United States of America

Find articles by Lama, V. in: PubMed | Google Scholar |

Published April 27, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.196651.
Copyright © 2026, Lu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 27, 2026 - Version history
View PDF
Abstract

Survival after lung transplantation is limited by chronic, progressive graft failure, termed chronic lung allograft dysfunction (CLAD). Graft-resident mesenchymal cells (MCs) drive CLAD pathogenesis and exhibit stable dysregulated signaling, yet the transcriptomic and epigenomic drivers underlying this fibrogenic transformation remain elusive. We used single-cell multi-omic profiling to characterize gene expression and chromatin accessibility in MCs isolated from lavage fluid of lung transplant recipients with and without CLAD, collected early post-transplantation or after disease onset. MCs obtained after CLAD onset demonstrated a distinct transcriptomic signature compared with non-CLAD controls, enabling classification of disease status at the single-cell level with > 98% accuracy using signature genes. Chromatin accessibility analyses identified enrichment of CCAAT-enhancer-binding protein family transcription factors, specifically CEBPD, in CLAD MCs. Early post-transplant MCs showed minimal accessibility differences, suggesting that CEBPD-associated regulatory changes emerge over time. Integration analyses identified eight MC states and a CLAD-specific shift towards a fibrotic state. CEBPD, SOX4, and FOXP2 were identified as putative regulators of this state with substantial overlap in predicted targets. Targeting CEBPD reversed fibrotic phenotypes of CLAD MCs (decreased ECM expression, contractility, proliferation, and migration). Together, these data provide insights into transcriptomic and epigenomic changes in post-transplant MCs, nominating biomarkers and therapeutic targets.

Supplemental material

View Unedited blot and gel images

View

Version history
  • Version 1 (April 27, 2026): In-Press Preview
Advertisement
Advertisement