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Transcriptomic investigation reveals donor specific gene signatures in human lung transplants

Cristina Baciu, Andrew Sage, Ricardo Zamel, Jason Shin, Xiao-Hui Bai, Olivia Hough, Mamatha Bhat, Jonathan C Yeung, Marcelo Cypel, Shaf Keshavjee, Mingyao Liu
European Respiratory Journal 2020; DOI: 10.1183/13993003.00327-2020
Cristina Baciu
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
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  • ORCID record for Cristina Baciu
Andrew Sage
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
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Ricardo Zamel
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
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Jason Shin
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
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Xiao-Hui Bai
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
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Olivia Hough
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
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Mamatha Bhat
2Multiorgan Transplant Program, University Health Network, Toronto, Canada
3Division of Gastroenterology, University of Toronto, Toronto, Canada
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Jonathan C Yeung
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
2Multiorgan Transplant Program, University Health Network, Toronto, Canada
4Toronto Lung Transplant Program, Department of Surgery, University of Toronto, Toronto, Canada
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Marcelo Cypel
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
2Multiorgan Transplant Program, University Health Network, Toronto, Canada
4Toronto Lung Transplant Program, Department of Surgery, University of Toronto, Toronto, Canada
5Institute of Medical Science, University of Toronto, Toronto, Canada
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Shaf Keshavjee
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
2Multiorgan Transplant Program, University Health Network, Toronto, Canada
4Toronto Lung Transplant Program, Department of Surgery, University of Toronto, Toronto, Canada
5Institute of Medical Science, University of Toronto, Toronto, Canada
6These authors share senior authorship
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Mingyao Liu
1Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
2Multiorgan Transplant Program, University Health Network, Toronto, Canada
4Toronto Lung Transplant Program, Department of Surgery, University of Toronto, Toronto, Canada
5Institute of Medical Science, University of Toronto, Toronto, Canada
6These authors share senior authorship
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Abstract

Rationale Transplantation of lungs from donation after circulatory death (DCD) in addition to donation after brain death (DBD) became routine worldwide to address the global organ shortage. The development of ex vivo lung perfusion (EVLP) for donor lung assessment and repair contributed to the increased use of DCD lungs. We hypothesise that better understanding of the differences between lungs from DBD and DCD donors, and between EVLP and directly transplanted (non-EVLP) lungs, will lead to discovery of the injury specific targets for donor lung repair and reconditioning.

Methods Tissue biopsies from human DBD (n=177) and DCD (n=65) donor lungs assessed with or without EVLP, were collected at the end of cold ischemic time. All samples were processed with microarray assay. Gene expression, network and pathway analyses were performed using R, Ingenuity Pathway Analysis and STRING. Results were validated with protein assay, multiple logistic regression and 10-fold cross validation.

Results Our analyses showed that lungs from DBD donors have up-regulation of inflammatory cytokines and pathways. In contrast, DCD lungs display a transcriptome signature of pathways associated with cell death, apoptosis and necrosis. Network centrality revealed specific drug targets to rehabilitate the DBD lungs. Moreover, in DBD lungs, TNFR1/2 signalling pathways and macrophage migration inhibitory factor associated pathways were activated in the EVLP group. A panel of genes that differentiate the EVLP from non-EVLP group in DBD lungs was identified.

Conclusion The examination of gene expression profiling indicates that DBD and DCD lungs have distinguishable biological transcriptome signatures.

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. Yan reports grants from National Institutes of Health, during the conduct of the study;.

Conflict of interest: Dr. Baciu has nothing to disclose.

Conflict of interest: Dr. Sage has nothing to disclose.

Conflict of interest: Dr. Zamel has nothing to disclose.

Conflict of interest: Dr. Shin has nothing to disclose.

Conflict of interest: Dr. Bai has nothing to disclose.

Conflict of interest: Dr. Hough has nothing to disclose.

Conflict of interest: Dr. Bhat has nothing to disclose.

Conflict of interest: Dr. Yeung has nothing to disclose.

Conflict of interest: Dr. Cypel has nothing to disclose.

Conflict of interest: Dr. Keshavjee reports grants from Canadian Institutes of Health Research, grants from Genome Canada, during the conduct of the study;.

Conflict of interest: Dr. Liu reports grants from Canadian Institutes of Health Research, grants from Genome Canada, during the conduct of the study;.

  • Received February 14, 2020.
  • Accepted October 5, 2020.
  • Copyright ©ERS 2020
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Transcriptomic investigation reveals donor specific gene signatures in human lung transplants
Cristina Baciu, Andrew Sage, Ricardo Zamel, Jason Shin, Xiao-Hui Bai, Olivia Hough, Mamatha Bhat, Jonathan C Yeung, Marcelo Cypel, Shaf Keshavjee, Mingyao Liu
European Respiratory Journal Jan 2020, 2000327; DOI: 10.1183/13993003.00327-2020

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Transcriptomic investigation reveals donor specific gene signatures in human lung transplants
Cristina Baciu, Andrew Sage, Ricardo Zamel, Jason Shin, Xiao-Hui Bai, Olivia Hough, Mamatha Bhat, Jonathan C Yeung, Marcelo Cypel, Shaf Keshavjee, Mingyao Liu
European Respiratory Journal Jan 2020, 2000327; DOI: 10.1183/13993003.00327-2020
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