title: Multiple paracrine factors secreted by mesenchymal stem cells contribute to angiogenesis.
abstract: The therapeutic effects of stem cell transplantation in ischemic disease are mediated by the production of paracrine bioactive factors. However, the bioactive factors secreted by human mesenchymal stem cells (hMSCs) and their angiogenic activity are not clearly identified or determined. We here found that hMSC-derived conditioned media (hMSC-CdM) stimulated in vitro angiogenic activity of endothelial cells and contained significant levels of various growth factors and cytokines, such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and transforming growth factor-beta1 (TGF-β1). The angiogenic activity of hMSC-CdM was significantly inhibited by pretreatment with neutralizing antibodies against VEGF, MCP-1, and IL-6, but not against TGF-β1 and HGF. A mixture of those inhibitory antibodies blocked CdM-mediated activation of angiogenic signals, as well as inhibited CdM-mediated in vivo angiogenesis. Moreover, local injection of CdM increased angiogenesis and promoted blood flow in mice with hindlimb ischemia, and these effects were inhibited by co-treatment with these inhibitory antibodies. These results indicate that hMSC-CdM represents a promising cell-free therapeutic strategy for neovascularization in ischemic diseases. These results suggest the combination of VEGF, MCP-1, and IL-6 as a commercial application for therapeutic angiogenesis.
authors.affiliation: Department of Obstetrics and Gynecology, Kangwon National University Hospital, Chuncheon, Gangwon-do 200-701, Republic of Korea.
authors.forename: Hyuk Min
authors.initials: HM
authors.lastname: Kwon
authors.affiliation: Departments of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, Republic of Korea.
authors.forename: Sung-Mo
authors.initials: SM
authors.lastname: Hur
authors.affiliation: Departments of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, Republic of Korea.
authors.forename: Keon-Young
authors.initials: KY
authors.lastname: Park
authors.affiliation: Departments of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, Republic of Korea.
authors.forename: Chun-Ki
authors.initials: CK
authors.lastname: Kim
authors.affiliation: Pharmicell Co., Ltd., Seongnam, Gyeonggi-do 462-737, Republic of Korea.
authors.forename: Yong-Man
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Pharmicell Co., Ltd., Seongnam, Gyeonggi-do 462-737, Republic of Korea.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Pharmicell Co., Ltd., Seongnam, Gyeonggi-do 462-737, Republic of Korea.
authors.forename: Ha-Cheol
authors.initials: HC
authors.lastname: Shin
authors.affiliation: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, Republic of Korea.
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.affiliation: Department of Obstetrics and Gynecology, Kangwon National University Hospital, Chuncheon, Gangwon-do 200-701, Republic of Korea.
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
authors.affiliation: Department of Biochemistry, College of Sciences, Yonsei University, Seoul 120-752, Republic of Korea.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.affiliation: Department of Obstetrics and Gynecology, Kangwon National University Hospital, Chuncheon, Gangwon-do 200-701, Republic of Korea.
authors.forename: Dong Heon
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Departments of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, Republic of Korea. Electronic address: ymkim@kangwon.ac.kr.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
mesh_terms: D000328:Adult; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007511:Ischemia / Q000628:therapy*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; HUVEC; Mesenchymal stem cell; Paracrine factor