title: The Therapeutic Effects of Human Mesenchymal Stem Cells Primed with Sphingosine-1 Phosphate on Pulmonary Artery Hypertension.
abstract: Stem cell (SC) therapy has become a potential treatment modality for pulmonary artery hypertension (PAH), but the efficacy of human SC and priming effects have not yet been established. The mobilization and homing of hematopoietic stem cells (HSCs) are modulated by priming factors that include a bioactive lipid, sphingosine-1-phosphate (S1P), which stimulates CXCR4 receptor kinase signaling. Here, we show that priming human mesenchymal stem cells (MSCs) with S1P enhances their therapeutic efficacy in PAH. Human MSCs, similar to HSCs, showed stronger chemoattraction to S1P in transwell assays. Concomitantly, MSCs treated with 0.2 μM S1P showed increased phosphorylation of both MAPKp42/44 and AKT protein compared with nonprimed MSCs. Furthermore, S1P-primed MSCs potentiated colony forming unit-fibroblast, anti-inflammatory, and angiogenic activities of MSCs in culture. In a PAH animal model induced by subcutaneously injected monocrotaline, administration of human cord blood-derived MSCs (hCB-MSCs) or S1P-primed cells significantly attenuated the elevated right ventricular systolic pressure. Notably, S1P-primed CB-MSCs, but not unprimed hCB-MSCs, also elicited a significant reduction in the right ventricular weight ratio and pulmonary vascular wall thickness. S1P-primed MSCs enhanced the expression of several genes responsible for stem cell trafficking and angiogenesis, increasing the density of blood vessels in the damaged lungs. Thus, this study demonstrates that human MSCs have potential utility for the treatment of PAH, and that S1P priming increases the effects of SC therapy by enhancing cardiac and vascular remodeling. By optimizing this protocol in future studies, SC therapy might form a basis for clinical trials to treat human PAH.
authors.affiliation: 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Hyunsook
authors.initials: H
authors.lastname: Kang
authors.affiliation: 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Kang-Hyun
authors.initials: KH
authors.lastname: Kim
authors.affiliation: 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Jisun
authors.initials: J
authors.lastname: Lim
authors.affiliation: 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Jinbeom
authors.initials: J
authors.lastname: Heo
authors.affiliation: 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Jongjin
authors.initials: J
authors.lastname: Choi
authors.affiliation: 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Jaeho
authors.initials: J
authors.lastname: Jeong
authors.affiliation: 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: YongHwan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: 4 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
authors.affiliation: 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Yeon-Mok
authors.initials: YM
authors.lastname: Oh
authors.affiliation: 5 Department of Urology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Myung-Soo
authors.initials: MS
authors.lastname: Choo
authors.affiliation: 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
authors.affiliation: 6 Department of Biomedical Research Center, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: 6 Department of Biomedical Research Center, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: 7 Biomedical Research Institute , Medipost Co., Ltd., Seoul, Korea.
authors.forename: Wonil
authors.initials: W
authors.lastname: Oh
authors.affiliation: 7 Biomedical Research Institute , Medipost Co., Ltd., Seoul, Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: 3 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Sei Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.|2 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.
authors.forename: Dong-Myung
authors.initials: DM
authors.lastname: Shin
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001794:Blood Pressure / Q000502:physiology; D002465:Cell Movement; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002478:Cells, Cultured; D006801:Humans; D006976:Hypertension, Pulmonary / Q000628:therapy*; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D016686:Monocrotaline; D018919:Neovascularization, Physiologic / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D066253:Vascular Remodeling / Q000502:physiology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D008246:Lysophospholipids; D014157:Transcription Factors; C478359:WDR77 protein, human; C060506:sphingosine 1-phosphate; D016686:Monocrotaline; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D013110:Sphingosine; D054804:Cathelicidins