Abstract
Bronchiolitis obliterans syndrome (BOS) is a fibrotic disease that is heavily responsible for the high mortality rates after lung transplantation. Myofibroblasts are primary effectors of this fibrotic process, but their origin is still debated. The purpose of this work was to identify the precursors of mesenchymal cells responsible for post-transplant airway fibro-obliteration.
Lineage-tracing tools were used to track or deplete potential sources of myofibroblasts in the heterotopic tracheal transplantation model. Allografts were analysed by histology, confocal microscopy, flow cytometry or single-cell transcriptomic analysis. BOS explants were evaluated by histology and confocal microscopy.
Myofibroblasts in the allografts were recipient-derived. When recipient mice were treated with tacrolimus, we observed rare epithelial-to-mesenchymal transition phenomena and an overall increase in donor-derived myofibroblasts (p=0.0467), but the proportion of these cells remained low (7%). Haematopoietic cells, and specifically the mononuclear phagocyte system, gave rise to the majority of myofibroblasts found in occluded airways. Ablation of Cx3cR1+ cells decreased fibro-obliteration (p=0.0151) and myofibroblast accumulation (p=0.0020). Single-cell RNA sequencing revealed similarities between myeloid-derived cells from allografts and both murine and human samples of lung fibrosis. Finally, myofibroblasts expressing the macrophage marker CD68 were increased in BOS explants when compared to controls (14.4% versus 8.5%, p=0.0249).
Recipient-derived myeloid progenitors represent a clinically relevant source of mesenchymal cells infiltrating the airways after allogeneic transplantation. Therapies targeting the mononuclear phagocyte system could improve long-term outcomes after lung transplantation.
Abstract
Bronchiolitis obliterans syndrome remains a major cause of mortality after lung transplantation. The mononuclear phagocyte system actively contributes to fibrotic occlusion of rejected airways, thereby representing a promising novel therapeutic target. https://bit.ly/3hQh8UL
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.04466-2020
This article has supplementary material available from erj.ersjournals.com
Data availability: Raw scRNA-seq data can be accessed on GEO (accession number GSE160760).
Author contributions: M-P. Di Campli performed most of the experiments and analysis. J. Scaillet, A. Assabban and A. Azouz contributed to some experiments. A. Azouz and M. Splittgerber performed bioinformatics analysis. M. Remmelink and A. Van Keymeulen helped with the interpretation of data and the conception of experiments. F. Libert performed next-generation sequencing sample processing and preliminary analysis. M-P. Di Campli, P. Lemaitre, A. Le Moine and S. Goriely conceived and designed the study. S. Goriely supervised the whole project. M-P. Di Campli and S. Goriely wrote the manuscript. All authors approved the final manuscript before submission.
Conflict of interest: M-P. Di Campli has nothing to disclose.
Conflict of interest: A. Azouz has nothing to disclose.
Conflict of interest: A. Assabban has nothing to disclose.
Conflict of interest: J. Scaillet has nothing to disclose.
Conflict of interest: M. Splittgerber has nothing to disclose.
Conflict of interest: A. Van Keymeulen has nothing to disclose.
Conflict of interest: F. Libert has nothing to disclose.
Conflict of interest: M. Remmelink has nothing to disclose.
Conflict of interest: A. Le Moine has nothing to disclose.
Conflict of interest: P. Lemaitre has nothing to disclose.
Conflict of interest: S. Goriely has nothing to disclose.
Support statement: This study was supported by the Fonds National de la Recherche Scientifique (FRS-FNRS, Belgium), the European Regional Development Fund (ERDF) of the Walloon Region (Wallonia-Biomed portfolio, 411132-957270), the Fonds pour la Chirurgie Cardiaque and the Fonds ERASME. S. Goriely is a senior research associate of the FRS-FNRS. M-P. Di Campli is supported by a FRIA-FNRS grant. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received February 17, 2020.
- Accepted September 16, 2020.
- Copyright ©ERS 2021
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