title: Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats.
abstract: OBJECTIVE
  Microvesicles (MVs) are nanoscale membrane fragments released from virtually all cell types upon activation or apoptosis, and may contribute to the beneficial effects of stem cell therapy. In this study, we investigated the therapeutic effects of mesenchymal stem cell (MSC) derived MVs (MSC-MVs) on pulmonary artery hypertension (PAH) in rats.
  
  
  METHODS
  MSC-MVs were isolated from rat bone marrow MSCs that were cultured in a serum-free conditioned medium. Transmission electron microscopy (TEM), flow cytometry and nanoparticle tracking analysis (NTA) were used to characterize the MVs. Adult SD rats were injected with monocrotaline (50 mg/kg, sc) to induce PAH. Three weeks later, the rats were intravenously injected with MSCs, MSC-MVs or saline for 2 weeks. At the end of treatments, the hemodynamic parameters and pathological right ventricular and pulmonary arterial remodeling were analyzed in each group.
  
  
  RESULTS
  The MSC-MVs showed general morphologic characteristics of MVs and expressed annexin V and CD29 markers under TEM, and their size ranged from 40 to 300 nm. Intravenous injection of MSC-MVs or MSCs significantly ameliorated the mean pulmonary artery pressure (mPAP) and mean right ventricle pressure (mRVP) in PAH rats. Furthermore, intravenous injection of MSC-MVs or MSCs significantly decreased the right ventricle (RV) hypertrophy and pulmonary arteriole area index (AI) and thickness index (TI) in PAH rats.
  
  
  CONCLUSIONS
  Intravenous injection of MSC-MVs or MSCs produces similar beneficial effects for treating PAH, and our results provide a basis for cell-free approach in stem cell therapy.
authors.affiliation: Department of Cardiology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Jian-ying
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Cardiology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Ran
authors.initials: R
authors.lastname: An
authors.affiliation: Department of Cardiology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Zhen-jun
authors.initials: ZJ
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Jin-ju
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Shu-zhen
authors.initials: SZ
authors.lastname: Chen
authors.affiliation: Department of Cardiology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Mian-ming
authors.initials: MM
authors.lastname: Hong
authors.affiliation: Department of Cardiology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Jing-hu
authors.initials: JH
authors.lastname: Liu
authors.affiliation: Department of Cardiology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Meng-yuan
authors.initials: MY
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Yan-fang
authors.initials: YF
authors.lastname: Chen
mesh_terms: D000818:Animals; D055252:Cell-Derived Microparticles / Q000502:physiology*; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000503:physiopathology* / Q000628:therapy*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D011651:Pulmonary Artery / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
references.citation: Circulation. 2012 Nov 27;126(22):2601-11
references.pmid: 23114789
references.citation: J Extracell Vesicles. 2013 Dec 23;2:
references.pmid: 24376909
references.citation: Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H1120-8
references.pmid: 16980338
references.citation: Stem Cells. 2013 Dec;31(12):2737-46
references.pmid: 23630198
references.citation: Circ Res. 2005 Mar 4;96(4):442-50
references.pmid: 15692087
references.citation: Hypertension. 2009 May;53(5):877-83
references.pmid: 19307469
references.citation: Nephrology (Carlton). 2012 Jul;17(5):493-500
references.pmid: 22369283
references.citation: J Huazhong Univ Sci Technolog Med Sci. 2012 Dec;32(6):810-817
references.pmid: 23271278
references.citation: J Proteomics. 2010 Sep 10;73(10):1907-20
references.pmid: 20601276
references.citation: Exp Ther Med. 2012 Nov;4(5):839-843
references.pmid: 23226736
references.citation: PLoS One. 2012;7(11):e50105
references.pmid: 23185548
references.citation: N Engl J Med. 2004 Oct 14;351(16):1655-65
references.pmid: 15483284
references.citation: J Extracell Vesicles. 2012 Apr 16;1:
references.pmid: 24009886
references.citation: J Cereb Blood Flow Metab. 2013 Nov;33(11):1711-5
references.pmid: 23963371
references.citation: PLoS One. 2010 Jul 27;5(7):e11803
references.pmid: 20668554
references.citation: Anal Biochem. 2012 Sep 1;428(1):44-53
references.pmid: 22691960
references.citation: Proc Am Thorac Soc. 2011 Jun;8(3):223-72
references.pmid: 21653527
references.citation: Oxid Med Cell Longev. 2013;2013:572729
references.pmid: 24288585
references.citation: Arthritis Rheum. 2005 Nov;52(11):3337-48
references.pmid: 16255015
references.citation: Nephrol Dial Transplant. 2011 May;26(5):1474-83
references.pmid: 21324974
references.citation: Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1606-16
references.pmid: 19783775
references.citation: Nat Cell Biol. 2007 Jun;9(6):654-9
references.pmid: 17486113
references.citation: Circulation. 2010 May 11;121(18):2045-66
references.pmid: 20458021
references.citation: Semin Respir Crit Care Med. 2005 Aug;26(4):429-36
references.pmid: 16121320
references.citation: Thromb Haemost. 2007 Mar;97(3):425-34
references.pmid: 17334510
references.citation: J Am Soc Nephrol. 2009 May;20(5):1053-67
references.pmid: 19389847
references.citation: Respir Res. 2007 Jan 30;8:8
references.pmid: 17263874
references.citation: Circulation. 2006 Jul 4;114(1 Suppl):I181-5
references.pmid: 16820570
references.citation: Stem Cells Dev. 2012 Dec 10;21(18):3289-97
references.pmid: 22839741
references.citation: Leukemia. 2006 Sep;20(9):1487-95
references.pmid: 16791265