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Infusion of Mesenchymal Stem Cells Protects Lung Transplants from Cold Ischemia-Reperfusion Injury in Mice

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Abstract

Background

Cold ischemia-reperfusion injury (IRI) is a major cause of graft failure in lung transplantation. Despite therapeutic benefits of mesenchymal stem cells (MSCs) in attenuating acute lung injury, their protection of lung transplants from cold IRI remains elusive. The present study was to test the efficacy of MSCs in the prevention of cold IRI using a novel murine model of orthotopic lung transplantation.

Methods

Donor lungs from C57BL/6 mice were exposed to 6 h of cold ischemia before transplanted to syngeneic recipients. MSCs were isolated from the bone marrows of C57BL/6 mice for recipient treatment. Gas exchange was determined by the measurement of blood oxygenation, and lung injury and inflammation were assessed by histological analyses.

Results

Intravenously delivered MSC migration/trafficking to the lung grafts occurred within 4-hours post-transplantation. As compared to untreated controls, the graft arterial blood oxygenation (PaO2/FiO2) capacity was significantly improved in MSC-treated recipients as early as 4 h post-reperfusion and such improvement continued over time. By 72 h, oxygenation reached normal level that was not seen in controls. MSCs treatment conferred significant protection of the grafts from cold IRI and cell apoptosis, which is correlated with less cellular infiltration, a decrease in proinflammatory cytokines (TNF-α, IL-6) and toll-like receptor 4, and an increase in anti-inflammatory TSG-6 generation.

Conclusions

MSCs provide significant protection against cold IRI in lung transplants, and thus may be a promising strategy to improve outcomes after lung transplantation.

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Abbreviations

ANOVA:

Analysis of variance

eGFF:

Enhanced green fluorescence protein

H&E:

Hematoxylin & eosin

MSCs:

Mesenchymal stem cells

IL:

Interleukin

IRI:

Ischemia-reperfusion injury

ROS:

Reactive oxygen species

SEM:

Standard error of mean

TNF:

Tumor necrosis factor

TLR:

Toll-like receptor

TSG:

Tumor necrosis factor-α stimulated gene/protein

TUNEL:

Terminal deoxynucleotyl transferase dUTP nick end labeling

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Acknowledgments

We are grateful to Dr. Bertha Garcia at Western University, London, Canada for her critical review of the histological slides, and to Drs. Shuhua Luo and Weihua Liu for their technical assistance. This work was supported by Grant to H.W. from National Natural Science Foundation of China (No. 81273257), and National High Technology Research and Development Program 863 (2012AA021003). C.D. was supported by grants from the Kidney Foundation of Canada and the Canadian Institutes of Health Research.

Conflict of interest

The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China

    Weijun Tian, Bai Zhang, Xiangchen Dai, Zhixiang Zhang & Hao Wang

  2. Department of Biology, Tianjin Medical University, Tianjin, China

    Yi Liu & Guang Li

  3. Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, China

    Xiaochun Li

  4. Tianjin General Surgery Institute, Tianjin, China

    Zhixiang Zhang & Hao Wang

  5. Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada

    Caigan Du

  6. Department of Urologic Sciences, The University of British Columbia, VGH-Jack Bell Research Centre, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada

    Caigan Du

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  1. Weijun Tian
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Correspondence to Caigan Du or Hao Wang.

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Tian, W., Liu, Y., Zhang, B. et al. Infusion of Mesenchymal Stem Cells Protects Lung Transplants from Cold Ischemia-Reperfusion Injury in Mice. Lung 193, 85–95 (2015). https://doi.org/10.1007/s00408-014-9654-x

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  • DOI: https://doi.org/10.1007/s00408-014-9654-x

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