title: A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles.
abstract: BACKGROUND
  The therapeutic potential of mesenchymal stromal cells (MSCs) may be largely mediated by paracrine factors contained in microvesicles (MV) released from intracellular endosomes. A systematic review of controlled interventional animal studies was performed to identify models of organ injury where clinical translation of MSC-derived microvesicle therapy appears most promising as regenerative therapy.
  
  
  METHODS
  A total of 190 published articles were identified in our systematic search of electronic databases (MEDLINE, EMBASE, PUBMED). After screening for eligibility, a total of 17 controlled studies testing MSC-derived MVs as therapeutic interventions in animal models of disease underwent comprehensive review, quality assessment, and data extraction.
  
  
  RESULTS
  Thirteen studies addressed the regenerative potential following organ injury. Six studies were included on acute kidney injury, 4 on myocardial infarction and reperfusion injury, 1 on hind limb ischemia, 1 on liver injury, and 1 on hypoxic lung injury. Four studies addressed immunological effects of MSC-derived MVs on inhibiting tumor growth. Twelve studies (71%) provided explicit information regarding the number of animals allocated to treatment or control groups. Five studies (29%) randomly assigned animals to treatment or control groups and only 1 study (6%) reported on blinding. Therapeutic intervention involved isolation of exosomes (40-100 nm) in eight studies, while nine studies tested unfractionated microvesicles (<1,000 nm). In studies of tissue regeneration, all 13 reported that treatment with MSC-derived MVs improved at least one major/clinical parameter associated with organ dysfunction. Three of 4 studies evaluating the inhibition of tumor growth reported benefit.
  
  
  CONCLUSIONS
  In preclinical studies, the use of MSC-derived MVs is strongly associated with improved organ function following injury and may be useful for inhibiting tumor growth. Improved preclinical study quality in terms of treatment allocation reporting, randomization and blinding will accelerate needed progress towards clinical trials that should assess feasibility and safety of this therapeutic approach in humans.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Celine
authors.initials: C
authors.lastname: Akyurekli
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Le
authors.forename: Richard B
authors.initials: RB
authors.lastname: Richardson
authors.forename: Dean
authors.initials: D
authors.lastname: Fergusson
authors.forename: Jason
authors.initials: J
authors.lastname: Tay
authors.forename: David S
authors.initials: DS
authors.lastname: Allan
mesh_terms: D058186:Acute Kidney Injury / Q000628:therapy*; D000818:Animals; D055252:Cell-Derived Microparticles / Q000637:transplantation*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009203:Myocardial Infarction / Q000628:therapy*; D015427:Reperfusion Injury / Q000628:therapy*; D016896:Treatment Outcome
references.citation: Stem Cells. 2012 Jul;30(7):1575-8
references.pmid: 22553154
references.citation: Stem Cells Dev. 2013 Mar 1;22(5):758-71
references.pmid: 23034046
references.citation: Nat Rev Immunol. 2014 Mar;14(3):195-208
references.pmid: 24566916
references.citation: PLoS Med. 2009 Jul 21;6(7):e1000097
references.pmid: 19621072
references.citation: Stem Cell Res. 2010 May;4(3):214-22
references.pmid: 20138817
references.citation: Stem Cells Dev. 2010 May;19(5):607-14
references.pmid: 19824807
references.citation: PLoS One. 2013 Dec 31;8(12):e84256
references.pmid: 24391924
references.citation: Stem Cells Dev. 2012 Oct 10;21(15):2789-97
references.pmid: 22533467
references.citation: Nat Biotechnol. 2014 May;32(5):490-5
references.pmid: 24752081
references.citation: PLoS One. 2013 Apr 12;8(4):e61366
references.pmid: 23593475
references.citation: Cell Transplant. 2012;21(8):1697-709
references.pmid: 22410280
references.citation: PLoS One. 2012;7(3):e33115
references.pmid: 22431999
references.citation: Stem Cells Dev. 2012 Jul 20;21(11):1863-76
references.pmid: 22309189
references.citation: Stem Cell Res. 2013 May;10(3):301-12
references.pmid: 23399448
references.citation: Nephrology (Carlton). 2012 Jul;17(5):493-500
references.pmid: 22369283
references.citation: J Am Soc Nephrol. 2009 May;20(5):1053-67
references.pmid: 19389847
references.citation: Stem Cells Dev. 2012 Sep 1;21(13):2410-9
references.pmid: 22455365
references.citation: Blood. 2007 Nov 15;110(10):3499-506
references.pmid: 17664353
references.citation: Circulation. 2012 Nov 27;126(22):2601-11
references.pmid: 23114789
references.citation: J Clin Invest. 2013 Apr;123(4):1542-55
references.pmid: 23454749
references.citation: Am J Physiol Lung Cell Mol Physiol. 2012 Dec 1;303(11):L967-77
references.pmid: 23023971
references.citation: Stem Cell Res Ther. 2013 Apr 25;4(2):34
references.pmid: 23618405
references.citation: Nucleic Acids Res. 2010 Jan;38(1):215-24
references.pmid: 19850715
references.citation: PLoS Med. 2013;10(7):e1001489
references.pmid: 23935460
references.citation: Cancer Lett. 2012 Feb 1;315(1):28-37
references.pmid: 22055459
references.citation: Nephrol Dial Transplant. 2011 May;26(5):1474-83
references.pmid: 21324974
references.citation: Ann N Y Acad Sci. 2012 Aug;1266:107-17
references.pmid: 22901262
references.citation: PLoS One. 2012;7(9):e44468
references.pmid: 22970226
references.citation: Curr Opin Nephrol Hypertens. 2010 Jan;19(1):7-12
references.pmid: 19823086
references.citation: Stem Cells Dev. 2013 Mar 15;22(6):845-54
references.pmid: 23002959
references.citation: Biochem Biophys Res Commun. 2009 Jan 16;378(3):433-8
references.pmid: 19028452
references.citation: Stem Cells. 2014 May;32(5):1074-82
references.pmid: 24860868
references.citation: PLoS One. 2012;7(9):e44092
references.pmid: 22970165
references.citation: Biochimie. 2013 Dec;95(12):2212-21
references.pmid: 23810910
references.citation: J Mol Cell Cardiol. 2010 Jun;48(6):1215-24
references.pmid: 20064522
references.citation: Stem Cells Dev. 2012 Dec 10;21(18):3289-97
references.pmid: 22839741
references.citation: PLoS One. 2012;7(10):e47559
references.pmid: 23133515
references.citation: Regen Med. 2011 Jul;6(4):481-92
references.pmid: 21749206
references.citation: Stem Cells. 2013 Sep;31(9):1731-6
references.pmid: 23766020