title: Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice.
abstract: Extracellular vesicles (EVs) from mice with monocrotaline (MCT)-induced pulmonary hypertension (PH) induce PH in healthy mice, and the exosomes (EXO) fraction of EVs from mesenchymal stem cells (MSCs) can blunt the development of hypoxic PH. We sought to determine whether the EXO fraction of EVs is responsible for modulating pulmonary vascular responses and whether differences in EXO-miR content explains the differential effects of EXOs from MSCs and mice with MCT-PH.
  
  
  
  Plasma, lung EVs from MCT-PH, and control mice were divided into EXO (exosome), microvesicle (MV) fractions and injected into healthy mice. EVs from MSCs were divided into EXO, MV fractions and injected into MCT-treated mice. PH was assessed by right ventricle-to-left ventricle + septum (RV/LV + S) ratio and pulmonary arterial wall thickness-to-diameter (WT/D) ratio. miR microarray analyses were also performed on all EXO populations. EXOs but not MVs from MCT-injured mice increased RV/LV + S, WT/D ratios in healthy mice. MSC-EXOs prevented any increase in RV/LV + S, WT/D ratios when given at the time of MCT injection and reversed the increase in these ratios when given after MCT administration. EXOs from MCT-injured mice and patients with idiopathic pulmonary arterial hypertension (IPAH) contained increased levels of miRs-19b,-20a,-20b, and -145, whereas miRs isolated from MSC-EXOs had increased levels of anti-inflammatory, anti-proliferative miRs including miRs-34a,-122,-124, and -127.
  
  
  
  These findings suggest that circulating or MSC-EXOs may modulate pulmonary hypertensive effects based on their miR cargo. The ability of MSC-EXOs to reverse MCT-PH offers a promising potential target for new PAH therapies.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA jason_aliotta@brown.edu jaliotta@lifespan.org.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Aliotta
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA.
authors.forename: Mandy
authors.initials: M
authors.lastname: Pereira
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA.
authors.forename: Sicheng
authors.initials: S
authors.lastname: Wen
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dooner
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Del Tatto
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Papa
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Goldberg
authors.affiliation: Lifespan Biostatistics Core, Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Grayson L
authors.initials: GL
authors.lastname: Baird
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Corey E
authors.initials: CE
authors.lastname: Ventetuolo
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Quesenberry
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Klinger
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D055252:Cell-Derived Microparticles / Q000378:metabolism / Q000637:transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055354:Exosomes / Q000235:genetics / Q000637:transplantation*; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000378:metabolism* / Q000503:physiopathology; D066253:Vascular Remodeling
chemical_list: D035683:MicroRNAs; D016686:Monocrotaline
keywords: Exosomes; Extracellular vesicles; Mesenchymal stem cells; MicroRNA; Pulmonary hypertension