title: Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation.
abstract: The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells "rehabilitated" marginal donor lungs rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose-dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co-administration of microvesicles with anti-CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs.
authors.affiliation: Department of Emergency Medicine, Grenoble University Hospital, La Tronche, France.
authors.forename: S
authors.initials: S
authors.lastname: Gennai
authors.affiliation: Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Monsel
authors.affiliation: Department of Anesthesiology, University of California San Francisco, San Francisco, CA.
authors.forename: Q
authors.initials: Q
authors.lastname: Hao
authors.affiliation: Department of Anesthesiology, University of California San Francisco, San Francisco, CA.
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Anesthesiology, University of California San Francisco, San Francisco, CA.|Departments of Medicine, Anesthesiology and Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA.
authors.forename: M A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Department of Anesthesiology, University of California San Francisco, San Francisco, CA.
authors.forename: J W
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000328:Adult; D055252:Cell-Derived Microparticles / Q000637:transplantation*; D002478:Cells, Cultured; D046148:Donor Selection; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008171:Lung Diseases / Q000150:complications / Q000601:surgery*; D016040:Lung Transplantation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D008875:Middle Aged; D009926:Organ Preservation; D010477:Perfusion; D011379:Prognosis; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D011654:Pulmonary Edema / Q000209:etiology / Q000628:therapy*; D009927:Tissue and Organ Procurement
keywords: lung failure/injury; stem cells; tissue injury and repair
references.citation: Expert Rev Respir Med. 2012 Feb;6(1):27-35
references.pmid: 22283576
references.citation: Am J Respir Crit Care Med. 2013 Apr 1;187(7):751-60
references.pmid: 23292883
references.citation: N Engl J Med. 2011 Apr 14;364(15):1431-40
references.pmid: 21488765
references.citation: J Biol Chem. 2010 Aug 20;285(34):26211-22
references.pmid: 20554518
references.citation: Mol Ther. 2010 Jul;18(7):1249-50
references.pmid: 20596063
references.citation: Arch Dermatol Res. 2010 Jul;302(5):367-74
references.pmid: 20035428
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16357-62
references.pmid: 19721001
references.citation: Cardiovasc Res. 2009 Jul 1;83(1):24-33
references.pmid: 19297368
references.citation: J Am Soc Nephrol. 2009 May;20(5):1053-67
references.pmid: 19389847
references.citation: Circulation. 2007 Oct 23;116(17):1896-906
references.pmid: 17923576
references.citation: Biochem Biophys Res Commun. 2007 Apr 20;355(4):956-62
references.pmid: 17336935
references.citation: Blood. 2006 Sep 15;108(6):2114-20
references.pmid: 16690970
references.citation: Nat Med. 2000 Apr;6(4):460-3
references.pmid: 10742156
references.citation: Cytotherapy. 2006;8(4):315-7
references.pmid: 16923606
references.citation: Stem Cells. 2006 Apr;24(4):928-35
references.pmid: 16306150
references.citation: Am J Respir Crit Care Med. 2005 Apr 1;171(7):786-91
references.pmid: 15665320
references.citation: Chest. 2005 Jan;127(1):161-5
references.pmid: 15653978
references.citation: Am J Respir Crit Care Med. 1999 Mar;159(3):980-8
references.pmid: 10051282
references.citation: Chest. 1998 Jul;114(1):51-60
references.pmid: 9674447
references.citation: Am Rev Respir Dis. 1988 Sep;138(3):720-3
references.pmid: 3202424
references.citation: J Proteome Res. 2012 Feb 3;11(2):839-49
references.pmid: 22148876
references.citation: Am J Respir Crit Care Med. 2001 May;163(6):1376-83
references.pmid: 11371404
references.citation: Am J Respir Crit Care Med. 2003 May 15;167(10):1440-50
references.pmid: 12738601
references.citation: Am J Physiol Lung Cell Mol Physiol. 2014 May 1;306(9):L809-15
references.pmid: 24532289
references.citation: Stem Cells. 2014 Jan;32(1):116-25
references.pmid: 23939814
references.citation: Microcirculation. 2014 Jan;21(1):84-92
references.pmid: 23952930
references.citation: Nat Med. 2012 Aug;18(8):1217-23
references.pmid: 22820644
references.citation: Int J Mol Med. 2013 Jun;31(6):1313-8
references.pmid: 23563270
references.citation: Stem Cell Res. 2013 May;10(3):301-12
references.pmid: 23399448
references.citation: PLoS One. 2012;7(3):e33115
references.pmid: 22431999
references.citation: Nat Med. 2012 May;18(5):759-65
references.pmid: 22504485
references.citation: Regen Med. 2013 Mar;8(2):197-209
references.pmid: 23477399
references.citation: Cell Mol Life Sci. 2011 Aug;68(16):2667-88
references.pmid: 21560073