Mesenchymal stromal cell therapy during ex vivo lung perfusion ameliorates ischemia-reperfusion injury in lung transplantation

Daisuke Nakajima, Yui Watanabe, Akihiro Ohsumi, Mauricio Pipkin, Manyin Chen, Pierre Mordant, Takashi Kanou, Tomohito Saito, Ryan Lam, Rafael Coutinho, Lindsay Caldarone, Stephen Juvet, Tereza Martinu, Rohin K. Iyer, John E. Davies, David M. Hwang, Thomas K. Waddell, Marcelo Cypel, Mingyao Liu, Shaf Keshavjee

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

BACKGROUND: The application of mesenchymal stromal cell (MSC)–based therapy during ex vivo lung perfusion (EVLP) could repair injured donor lungs before transplantation. The aim of this study was to determine the efficacy of MSC therapy performed during EVLP on ischemia-reperfusion injury using a pig lung transplant model. METHODS: Following 24 hours of cold storage, pig lungs were randomly assigned to 2 groups (n = 6 each), the control group without MSC vs the MSC group, where 5 × 106 cells/kg MSCs were delivered through the pulmonary artery during EVLP. After 12 hours of EVLP, followed by a 1-hour second cold preservation period, the left lung was transplanted and reperfused for 4 hours. RESULTS: EVLP perfusate hepatocyte growth factor (HGF) level at 12 hours was significantly elevated in the MSC group compared with the control and was associated with a significant decrease in cell death markers, cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling–positive cells, in the MSC group. The MSC group showed significantly lower interleukin (IL)-18 and interferon gamma levels and a significantly higher IL-4 level in lung tissue at 12 hours of EVLP than the control group. After transplantation, the MSC group showed a significant increase in lung tissue HGF level compared with the control group, associated with a significantly reduced lung tissue wet-to-dry weight ratio. Lung tissue tumor necrosis factor-α level and pathological acute lung injury score were significantly lower in the MSC group than the control group. CONCLUSIONS: The administration of MSCs ameliorated ischemic injury in donor lungs during EVLP and attenuated the subsequent ischemia-reperfusion injury after transplantation.

Original languageEnglish
Pages (from-to)1214-1223
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume38
Issue number11
DOIs
Publication statusPublished - 2019 Nov

Keywords

  • cell death
  • cytokine
  • hepatocyte growth factor
  • indoleamine 2,3-dioxygenase
  • inflammation

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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