Single-nuclei RNA-seq reveals aberrant cell populations in restrictive allograft syndrome after lung transplantation

Transplantation, pp. OA985

Abstract

* contributed equally Introduction: The pathogenesis of restrictive allograft syndrome (RAS), the most severe and progressive phenotype of chronic lung allograft dysfunction, remains unclear. Aim: To analyze the cellularly-resolved transcriptomic and histologic features in the human RAS lung and their relevance for the pathophysiology of RAS. Methods: Peripheral lung tissues from 15 patients undergoing lung re-transplantation and 9 control lungs were studied by snRNA-seq (10x Genomics). Findings were validated by immunofluorescent microscopy. Results: snRNA-seq data revealed IPF-associated aberrant basaloid cells, ectopic COL15A1+ endothelial cells (ECs), and CTHRC1+ fibrotic fibroblasts in RAS lungs. In contrast to IPF, features of bronchiolization are completely lacking. Aberrant basaloid and intermediate epithelial cell populations are characterized by therapeutically modifiable expression patterns, including integrin αvβ6, the activator of TGFβ. Histologic stainings confirmed our transcriptomic discoveries and disclosed distinctive distribution patterns with e.g., aberrant basaloid cells being localized at the edge of the fibrotic pushing border in RAS. Conclusions: RAS is characterized by uniquely distributed aberrant basaloid cells, ectopic COL15A1+ ECs, and CTHRC1+ fibrotic fibroblasts, populations previously found in IPF, making these cell types the prime target for therapeutic interventions. erj;64/suppl_68/OA985/F1 F1 F1

Authors 12

1. Lena Maureen Leiber

   Medizinische Hochschule Hannover · German Center for Lung Research

   Affiliation as printed

   1Respiratory Medicine, Hannover Medical School; German Center for Lung Research (Hannover, Germany), Hannover, Germany

2. Leonard Christian

   Medizinische Hochschule Hannover · German Center for Lung Research

   Affiliation as printed

   1Respiratory Medicine, Hannover Medical School; German Center for Lung Research (Hannover, Germany), Hannover, Germany

3. Lavinia Neubert

   Medizinische Hochschule Hannover · German Center for Lung Research

   Affiliation as printed

   2Institute of Pathology, Hannover Medical School; German Center for Lung Research (Hannover, Germany), Hannover, Germany

4. Hande Yilmaz

   Medizinische Hochschule Hannover · German Center for Lung Research

   Affiliation as printed

   1Respiratory Medicine, Hannover Medical School; German Center for Lung Research (Hannover, Germany), Hannover, Germany

5. Jan C. Kamp

   Medizinische Hochschule Hannover · German Center for Lung Research

   Affiliation as printed

   3Respiratory Medicine, Hannover Medical School; Institute of Pathology, Hannover Medical School; German Center for Lung Research (Hannover, Germany), Hannover, Germany

6. Edith Katharina Plucinski

   Medizinische Hochschule Hannover · German Center for Lung Research

   Affiliation as printed

   2Institute of Pathology, Hannover Medical School; German Center for Lung Research (Hannover, Germany), Hannover, Germany

7. Tobias Welte

   Medizinische Hochschule Hannover · German Center for Lung Research

   Affiliation as printed

   1Respiratory Medicine, Hannover Medical School; German Center for Lung Research (Hannover, Germany), Hannover, Germany

8. Christine Susanne Falk

   Medizinische Hochschule Hannover

   Affiliation as printed

   4Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany

9. Naftali Kaminski

   Yale University

   Affiliation as printed

   5Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine (New Haven, CT, USA), New Haven, United States

10. Danny David Jonigk corresponding Aachen 6Institute of Pathology German Center for Lung Research (Hannover

    RWTH Aachen University · Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    6Institute of Pathology, RWTH Aachen; Institute of Pathology, Hannover Medical School; German Center for Lung Research (Hannover, Germany), Aachen, Germany

11. Jens Gottlieb corresponding

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    1Respiratory Medicine, Hannover Medical School; German Center for Lung Research (Hannover, Germany), Hannover, Germany

12. Jonas C. Schupp corresponding

    Yale University · Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    7Respiratory Medicine, Hannover Medical School; German Center for Lung Research (Hannover, Germany); Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine (New Haven, CT, USA), Hannover, Germany