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Respiratory Research
Published in: Respiratory Research 1/2017

Open Access 01-12-2017 | Research

Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia-reperfusion injury and enhance reconditioning of donor lungs after circulatory death

Authors: Matthew L. Stone, Yunge Zhao, J. Robert Smith, Mark L. Weiss, Irving L. Kron, Victor E. Laubach, Ashish K. Sharma

Published in: Respiratory Research | Issue 1/2017

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Abstract

Background

Lung ischemia-reperfusion (IR) injury after transplantation as well as acute shortage of suitable donor lungs are two critical issues impacting lung transplant patients. This study investigates the anti-inflammatory and immunomodulatory role of human mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) to attenuate lung IR injury and improve of ex-vivo lung perfusion (EVLP)-mediated rehabilitation in donation after circulatory death (DCD) lungs.

Methods

C57BL/6 wild-type (WT) mice underwent sham surgery or lung IR using an in vivo hilar-ligation model with or without MSCs or EVs. In vitro studies used primary iNKT cells and macrophages (MH-S cells) were exposed to hypoxia/reoxygenation with/without co-cultures with MSCs or EVs. Also, separate groups of WT mice underwent euthanasia and 1 h of warm ischemia and stored at 4 °C for 1 h followed by 1 h of normothermic EVLP using Steen solution or Steen solution containing MSCs or EVs.

Results

Lungs from MSCs or EV-treated mice had significant attenuation of lung dysfunction and injury (decreased edema, neutrophil infiltration and myeloperoxidase levels) compared to IR alone. A significant decrease in proinflammatory cytokines (IL-17, TNF-α, CXCL1 and HMGB1) and upregulation of keratinocyte growth factor, prostaglandin E2 and IL-10 occurred in the BAL fluid from MSC or EV-treated mice after IR compared to IR alone. Furthermore, MSCs or EVs significantly downregulated iNKT cell-produced IL-17 and macrophage-produced HMGB1 and TNF-α after hypoxia/reoxygenation. Finally, EVLP of DCD lungs with Steen solution including MSCs or EVs provided significantly enhanced protection versus Steen solution alone. Co-cultures of MSCs or EVs with lung endothelial cells prevents neutrophil transendothelial migration after exposure to hypoxia/reoxygenation and TNF-α/HMGB1 cytomix.

Conclusions

These results suggest that MSC-derived EVs can attenuate lung inflammation and injury after IR as well as enhance EVLP-mediated reconditioning of donor lungs. The therapeutic benefits of EVs are in part mediated through anti-inflammatory promoting mechanisms via attenuation of immune cell activation as well as prevention of endothelial barrier integrity to prevent lung edema. Therefore, MSC-derived EVs offer a potential therapeutic strategy to treat post-transplant IR injury as well as rehabilitation of DCD lungs.
Literature
1.
Yusen RD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb SB, Levvey BJ, Lund LH, Meiser B, Rossano JW, Stehlik J. The registry of the International Society for Heart and Lung Transplantation: thirty-second official adult lung and heart-lung transplantation report--2015; focus theme: early graft failure. J Heart Lung Transplant. 2015;34:1264–77.CrossRefPubMed
2.
de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med. 2003;167:490–511.CrossRefPubMed
3.
Sharma AK, LaPar DJ, Zhao Y, Li L, Lau CL, Kron IL, Iwakura Y, Okusa MD, Laubach VE. Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury. Am J Respir Crit Care Med. 2011;183:1539–49.CrossRefPubMedPubMedCentral
4.
Sharma AK, LaPar DJ, Stone ML, Zhao Y, Kron IL, Laubach VE. Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury. Am J Transplant. 2013;13:2255–67.CrossRefPubMedPubMedCentral
5.
Abreu SC, Antunes MA, Xisto DG, Cruz FF, Branco VC, Bandeira E, Zola Kitoko J, de Araujo AF, Dellatorre-Texeira L, Olsen PC, et al. Bone marrow, adipose, and lung tissue-derived Murine Mesenchymal Stromal cells release different mediators and differentially affect airway and lung parenchyma in experimental asthma. Stem Cells Transl Med. 2017;6:1557–67.CrossRefPubMedPubMedCentral
6.
Aliotta JM, Pereira M, Wen S, Dooner MS, Del Tatto M, Papa E, Cheng Y, Goldberg L, Ventetuolo CE, Liang O, et al. Bone marrow endothelial progenitor cells are the cellular mediators of pulmonary hypertension in the Murine Monocrotaline injury model. Stem Cells Transl Med. 2017;6:1595–606.CrossRefPubMedPubMedCentral
7.
Morrison TJ, Jackson MV, Cunningham EK, Kissenpfennig A, McAuley DF, O’Kane CM, Krasnodembskaya AD. Mesenchymal Stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am J Respir Crit Care Med. 2017;196(10):1275–86.CrossRefPubMed
8.
Reiter J, Drummond S, Sammour I, Huang J, Florea V, Dornas P, Hare JM, Rodrigues CO, Young KC. Stromal derived factor-1 mediates the lung regenerative effects of mesenchymal stem cells in a rodent model of bronchopulmonary dysplasia. Respir Res. 2017;18:137.CrossRefPubMedPubMedCentral
9.
Kubo H. Extracellular vesicles in lung disease. Chest. 2017;
10.
Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.PubMed
11.
de Perrot M, Keshavjee S. Lung transplantation. Lung preservation. Chest Surg Clin N Am. 2003;13:443–62.CrossRefPubMed
12.
Charles EJ, Huerter ME, Wagner CE, Sharma AK, Zhao Y, Stoler MH, Mehaffey JH, Isbell JM, Lau CL, Tribble CG, et al. Donation after circulatory death lungs transplantable up to six hours after ex vivo lung perfusion. Ann Thorac Surg. 2016;102:1845–53.CrossRefPubMedPubMedCentral
13.
Cypel M, Rubacha M, Yeung J, Hirayama S, Torbicki K, Madonik M, Fischer S, Hwang D, Pierre A, Waddell TK, et al. Normothermic ex vivo perfusion prevents lung injury compared to extended cold preservation for transplantation. Am J Transplant. 2009;9:2262–9.CrossRefPubMed
14.
Mulloy DP, Stone ML, Crosby IK, Lapar DJ, Sharma AK, Webb DV, Lau CL, Laubach VE, Kron IL. Ex vivo rehabilitation of non-heart-beating donor lungs in preclinical porcine model: delayed perfusion results in superior lung function. J Thorac Cardiovasc Surg. 2012;144:1208–15.CrossRefPubMedPubMedCentral
15.
Cypel M, Yeung JC, Liu M, Anraku M, Chen F, Karolak W, Sato M, Laratta J, Azad S, Madonik M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011;364:1431–40.CrossRefPubMed
16.
Sharma AK, LaPar DJ, Stone ML, Zhao Y, Mehta CK, Kron IL, Laubach VE. NOX2 activation of natural killer T cells is blocked by the adenosine A2A receptor to inhibit lung ischemia-reperfusion injury. Am J Respir Crit Care Med. 2016;193:988–99.CrossRefPubMedPubMedCentral
17.
Stone ML, Sharma AK, Mas VR, Gehrau RC, Mulloy DP, Zhao Y, Lau CL, Kron IL, Huerter ME, Laubach VE. Ex vivo perfusion with adenosine A2A receptor agonist enhances rehabilitation of Murine donor lungs after circulatory death. Transplantation. 2015;99:2494–503.CrossRefPubMedPubMedCentral
18.
Yang Z, Sharma AK, Linden J, Kron IL, Laubach VE. CD4+ T lymphocytes mediate acute pulmonary ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2009;137:695–702. discussion 702CrossRefPubMedPubMedCentral
19.
Sharma AK, Salmon MD, Lu G, Su G, Pope NH, Smith JR, Weiss ML, Upchurch GR Jr. Mesenchymal stem cells attenuate NADPH Oxidase-dependent high mobility group box 1 production and inhibit abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2016;36:908–18.CrossRefPubMedPubMedCentral
20.
Smith JR, Cromer A, Weiss ML. Human umbilical cord Mesenchymal Stromal cell isolation, expansion, cryopreservation, and characterization. Curr Protoc Stem Cell Biol. 2017;41:1F 18 11–11F 18 23.
21.
Smith JR, Pfeifer K, Petry F, Powell N, Delzeit J, Weiss ML. Standardizing umbilical cord Mesenchymal Stromal cells for translation to clinical use: selection of GMP-compliant medium and a simplified isolation method. Stem Cells Int. 2016;2016:6810980.PubMedPubMedCentral
22.
Erdbrugger U, Rudy CK, Etter ME, Dryden KA, Yeager M, Klibanov AL, Lannigan J. Imaging flow cytometry elucidates limitations of microparticle analysis by conventional flow cytometry. Cytometry A. 2014;85:756–70.CrossRefPubMed
23.
Bruno S, Grange C, Collino F, Deregibus MC, Cantaluppi V, Biancone L, Tetta C, Camussi G. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One. 2012;7:e33115.CrossRefPubMedPubMedCentral
24.
Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, Sdrimas K, Fernandez-Gonzalez A, Kourembanas S. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012;126:2601–11.CrossRefPubMedPubMedCentral
25.
Sharma AK, Fernandez LG, Awad AS, Kron IL, Laubach VE. Proinflammatory response of alveolar epithelial cells is enhanced by alveolar macrophage-produced TNF-alpha during pulmonary ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol. 2007;293:L105–13.CrossRefPubMed
26.
Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, Mysliwietz J, Tonn JC, Goldbrunner R, Lonning PE, et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009;69:5331–9.CrossRefPubMed
27.
Prockop DJ, Brenner M, Fibbe WE, Horwitz E, Le Blanc K, Phinney DG, Simmons PJ, Sensebe L, Keating A. Defining the risks of mesenchymal stromal cell therapy. Cytotherapy. 2010;12:576–8.CrossRefPubMed
28.
Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F 3rd. Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells. 2011;29:11–9.CrossRefPubMed
29.
Biancone L, Bruno S, Deregibus MC, Tetta C, Camussi G. Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant. 2012;27:3037–42.CrossRefPubMed
30.
Cantaluppi V, Gatti S, Medica D, Figliolini F, Bruno S, Deregibus MC, Sordi A, Biancone L, Tetta C, Camussi G. Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells. Kidney Int. 2012;82:412–27.CrossRefPubMed
31.
Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C, Camussi G. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant. 2011;26:1474–83.CrossRefPubMed
32.
Zou X, Zhang G, Cheng Z, Yin D, Du T, Ju G, Miao S, Liu G, Lu M, Zhu Y. Microvesicles derived from human Wharton's jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther. 2014;5:40.CrossRefPubMedPubMedCentral
33.
Monsel A, Zhu YG, Gennai S, Hao Q, Hu S, Rouby JJ, Rosenzwajg M, Matthay MA, Lee JW. Therapeutic effects of human Mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med. 2015;192:324–36.CrossRefPubMedPubMedCentral
34.
Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15:42–9.CrossRefPubMed
35.
McAuley DF, Cross LM, Hamid U, Gardner E, Elborn JS, Cullen KM, Dushianthan A, Grocott MP, Matthay MA, O'Kane CM. Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med. 2017;5:484–91.CrossRefPubMed
36.
Zhu YG, Feng XM, Abbott J, Fang XH, Hao Q, Monsel A, Qu JM, Matthay MA, Lee JW. Human mesenchymal stem cell microvesicles for treatment of Escherichia Coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014;32:116–25.CrossRefPubMedPubMedCentral
37.
Gennai S, Monsel A, Hao Q, Park J, Matthay MA, Lee JW. Microvesicles derived from human Mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Transplant. 2015;15:2404–12.CrossRefPubMedPubMedCentral
38.
Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM, Stolz DB, Watkins SC, Di YP, Leikauf GD, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472.CrossRefPubMedPubMedCentral
39.
Mordant P, Nakajima D, Kalaf R, Iskender I, Maahs L, Behrens P, Coutinho R, Iyer RK, Davies JE, Cypel M, et al. Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation. J Heart Lung Transplant. 2016;35:1245–54.CrossRefPubMed
40.
Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 2015;77:13–27.CrossRefPubMed
41.
Collino F, Deregibus MC, Bruno S, Sterpone L, Aghemo G, Viltono L, Tetta C, Camussi G. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One. 2010;5:e11803.CrossRefPubMedPubMedCentral
42.
Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB, Farber DB. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One. 2009;4:e4722.CrossRefPubMedPubMedCentral
43.
Zhang W, Zhou T, Ma SF, Machado RF, Bhorade SM, Garcia JG. MicroRNAs implicated in Dysregulation of gene expression following human lung transplantation. Transl Respir Med. 2013;1:1.CrossRef
44.
Weiss JB, Eisenhardt SU, Stark GB, Bode C, Moser M, Grundmann S. MicroRNAs in ischemia-reperfusion injury. Am J Cardiovasc Dis. 2012;2:237–47.PubMedPubMedCentral
45.
Zhou L, Zang G, Zhang G, Wang H, Zhang X, Johnston N, Min W, Luke P, Jevnikar A, Haig A, Zheng X. MicroRNA and mRNA signatures in ischemia reperfusion injury in heart transplantation. PLoS One. 2013;8:e79805.CrossRefPubMedPubMedCentral
46.
Nana-Sinkam SP, Karsies T, Riscili B, Ezzie M, Piper M. Lung microRNA: from development to disease. Expert Rev Respir Med. 2009;3:373–85.CrossRefPubMed
47.
Varga ZV, Zvara A, Farago N, Kocsis GF, Pipicz M, Gaspar R, Bencsik P, Gorbe A, Csonka C, Puskas LG, et al. MicroRNAs associated with ischemia-reperfusion injury and cardioprotection by ischemic pre- and postconditioning: protectomiRs. Am J Physiol Heart Circ Physiol. 2014;307:H216–27.CrossRefPubMed
48.
Yu B, Gong M, Wang Y, Millard RW, Pasha Z, Yang Y, Ashraf M, Xu M. Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles. PLoS One. 2013;8:e73304.CrossRefPubMedPubMedCentral
49.
50.
51.
Feng Y, Huang W, Meng W, Jegga AG, Wang Y, Cai W, Kim HW, Pasha Z, Wen Z, Rao F, et al. Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1/miR-34a/HSP70 pathway. Stem Cells. 2014;32:462–72.CrossRefPubMedPubMedCentral
52.
Feng Y, Huang W, Wani M, Yu X, Ashraf M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One. 2014;9:e88685.CrossRefPubMedPubMedCentral
53.
Sharma AK, Zhao Y, Gehrau RC, Weiss ML, Mas VR, Laubach VE, Kron IL, Lau CL. Human mesenchymal stem cells modulate miR-206 and attanuate lung ischemia-reperfusion injury. Am J Respir Crit Care Med. 2015;191 Abstract presented at American Thoracic Society International Conference
54.
Cypel M, Keshavjee S. The clinical potential of ex vivo lung perfusion. Expert Rev Respir Med. 2012;6:27–35.CrossRefPubMed
55.
Emaminia A, Lapar DJ, Zhao Y, Steidle JF, Harris DA, Laubach VE, Linden J, Kron IL, Lau CL. Adenosine a(2)a agonist improves lung function during ex vivo lung perfusion. Ann Thorac Surg. 2011;92:1840–6.CrossRefPubMedPubMedCentral
56.
LaPar DJ, Laubach VE, Emaminia A, Crosby IK, Hajzus VA, Sharma AK, Sumner HM, Webb DV, Lau CL, Kron IL. Pretreatment strategy with adenosine A2A receptor agonist attenuates reperfusion injury in a preclinical porcine lung transplantation model. J Thorac Cardiovasc Surg. 2011;142:887–94.CrossRefPubMedPubMedCentral
57.
McAuley DF, Curley GF, Hamid UI, Laffey JG, Abbott J, McKenna DH, Fang X, Matthay MA, Lee JW. Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Physiol Lung Cell Mol Physiol. 2014;306:L809–15.CrossRefPubMedPubMedCentral
58.
Fan L, Benson HL, Vittal R, Mickler EA, Presson R, Fisher AJ, Cummings OW, Heidler KM, Keller MR, Burlingham WJ, Wilkes DS. Neutralizing IL-17 prevents obliterative bronchiolitis in murine orthotopic lung transplantation. Am J Transplant. 2011;11:911–22.CrossRefPubMedPubMedCentral
59.
Burlingham WJ, Love RB, Jankowska-Gan E, Haynes LD, Xu Q, Bobadilla JL, Meyer KC, Hayney MS, Braun RK, Greenspan DS, et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007;117:3498–506.CrossRefPubMedPubMedCentral
Metadata
Title
Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia-reperfusion injury and enhance reconditioning of donor lungs after circulatory death
Authors
Matthew L. Stone
Yunge Zhao
J. Robert Smith
Mark L. Weiss
Irving L. Kron
Victor E. Laubach
Ashish K. Sharma
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2017
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-017-0704-9

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