The mononuclear phagocyte system contributes to fibrosis in post-transplant Obliterans Bronchiolitis
- Maria-Pia Di Campli1,2,
- Abdulkader Azouz1,
- Assiya Assabban1,
- Jessika Scaillet1,
- Marion Splittgerber1,
- Alexandra Van Keymeulen3,
- Frederick Libert4,
- Myriam Remmelink5,
- Alain Le Moine1,
- Philippe Lemaitre6 and
- Stanislas Goriely1⇑
- 1ULB Center for Research in Immunology (U-CRI), Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium
- 2Department of Surgery, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
- 3Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles, Brussels, Belgium
- 4BRIGHTcore ULB VUB and Institute of Interdisciplinary Research in Human and Molecular Biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium
- 5Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
- 6Division of Thoracic Surgery, Lung Transplant Program, Columbia University Medical Center, New York, NY, USA
- S. Goriely, Institute for Medical Immunology, 8 rue Adrienne Bolland, B-6041 Charleroi-Gosselies, Belgium. E-mail: stgoriel{at}ulb.ac.be
Abstract
Bronchiolitis Obliterans Syndrome (BOS) is a fibrotic disease heavily responsible for high mortality rates after lung transplantation. Myofibroblasts are primary effectors of this fibrotic process, but their origin is still under debate. 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. Still, 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%). Hematopoietic 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 myofibroblasts accumulation (p=0.0020). Single-cell RNA-sequencing unveiled 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. Therefore, therapies targeting the mononuclear phagocyte system could improve long-term outcomes after lung transplantation.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Di Campli has nothing to disclose.
Conflict of interest: Dr. Azouz has nothing to disclose.
Conflict of interest: Dr. Assabban has nothing to disclose.
Conflict of interest: Dr. Scaillet has nothing to disclose.
Conflict of interest: Dr. Splittgerber has nothing to disclose.
Conflict of interest: Dr. Van Keymeulen has nothing to disclose.
Conflict of interest: Dr. Libert has nothing to disclose.
Conflict of interest: Dr. Remmelink has nothing to disclose.
Conflict of interest: Dr. Le Moine has nothing to disclose.
Conflict of interest: Dr. Lemaitre has nothing to disclose.
Conflict of interest: Dr. Goriely has nothing to disclose.
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- Received February 17, 2020.
- Accepted September 15, 2020.
- Copyright ©ERS 2020