title: BMP9 Induces Cord Blood-Derived Endothelial Progenitor Cell Differentiation and Ischemic Neovascularization via ALK1.
abstract: OBJECTIVE
  Modulating endothelial progenitor cells (EPCs) is essential for therapeutic angiogenesis, and thus various clinical trials involving EPCs are ongoing. However, the identification of environmental conditions and development of optimal methods are required to accelerate EPC-driven vasculogenesis.
  
  
  RESULTS
  We evaluated gene expression profiles of cord blood-derived EPCs and endothelial cells to identify the key factors in EPC→endothelial cell differentiation and to show that transforming growth factor-β family members contribute to EPC differentiation. The expression levels of activin receptor-like kinase 1 (ALK1) and its high-affinity ligand, bone morphogenetic protein 9 (BMP9) were markedly changed in EPC→endothelial cell differentiation. Interestingly, BMP9 induced EPC→endothelial cell differentiation and EPC incorporation into vessel-like structures by acting on ALK1 expressed on EPCs in vitro. BMP9 also induced neovascularization in mice with hindlimb ischemia by increasing vessel formation and the incorporation of EPCs into vessels. Conversely, neovascularization was impaired when ALK1 signaling was blocked. Furthermore, EPCs exposed to either short- or long-term BMP9 stimulation demonstrated these functions in EPC-mediated neovascularization.
  
  
  CONCLUSIONS
  Collectively, our results indicated that BMP9/ALK1 augmented vasculogenesis and angiogenesis, and thereby enhanced neovascularization. Thus, we suggest that BMP9/ALK1 may improve the efficacy of EPC-based therapies for treating ischemic diseases.
authors.affiliation: From the Department of Biochemistry, College of Life Science and Biotechnology (J.K., Y.J., W.-b.L., H.P., Y.-G.K.) and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine (J.-Y.K.), Yonsei University, Seoul, Korea; School of Interdisciplinary Biosciences and Bioengineering, Pohang University of Science and Technology, Pohang, Korea (M.K., D.H.); Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea (M.K.); and Department of new Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea (D.H.).
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: From the Department of Biochemistry, College of Life Science and Biotechnology (J.K., Y.J., W.-b.L., H.P., Y.-G.K.) and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine (J.-Y.K.), Yonsei University, Seoul, Korea; School of Interdisciplinary Biosciences and Bioengineering, Pohang University of Science and Technology, Pohang, Korea (M.K., D.H.); Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea (M.K.); and Department of new Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea (D.H.).
authors.forename: Minhyung
authors.initials: M
authors.lastname: Kim
authors.affiliation: From the Department of Biochemistry, College of Life Science and Biotechnology (J.K., Y.J., W.-b.L., H.P., Y.-G.K.) and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine (J.-Y.K.), Yonsei University, Seoul, Korea; School of Interdisciplinary Biosciences and Bioengineering, Pohang University of Science and Technology, Pohang, Korea (M.K., D.H.); Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea (M.K.); and Department of new Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea (D.H.).
authors.forename: Yoonjeong
authors.initials: Y
authors.lastname: Jeong
authors.affiliation: From the Department of Biochemistry, College of Life Science and Biotechnology (J.K., Y.J., W.-b.L., H.P., Y.-G.K.) and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine (J.-Y.K.), Yonsei University, Seoul, Korea; School of Interdisciplinary Biosciences and Bioengineering, Pohang University of Science and Technology, Pohang, Korea (M.K., D.H.); Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea (M.K.); and Department of new Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea (D.H.).
authors.forename: Wook-Bin
authors.initials: WB
authors.lastname: Lee
authors.affiliation: From the Department of Biochemistry, College of Life Science and Biotechnology (J.K., Y.J., W.-b.L., H.P., Y.-G.K.) and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine (J.-Y.K.), Yonsei University, Seoul, Korea; School of Interdisciplinary Biosciences and Bioengineering, Pohang University of Science and Technology, Pohang, Korea (M.K., D.H.); Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea (M.K.); and Department of new Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea (D.H.).
authors.forename: Hyojin
authors.initials: H
authors.lastname: Park
authors.affiliation: From the Department of Biochemistry, College of Life Science and Biotechnology (J.K., Y.J., W.-b.L., H.P., Y.-G.K.) and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine (J.-Y.K.), Yonsei University, Seoul, Korea; School of Interdisciplinary Biosciences and Bioengineering, Pohang University of Science and Technology, Pohang, Korea (M.K., D.H.); Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea (M.K.); and Department of new Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea (D.H.).
authors.forename: Ja-Young
authors.initials: JY
authors.lastname: Kwon
authors.affiliation: From the Department of Biochemistry, College of Life Science and Biotechnology (J.K., Y.J., W.-b.L., H.P., Y.-G.K.) and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine (J.-Y.K.), Yonsei University, Seoul, Korea; School of Interdisciplinary Biosciences and Bioengineering, Pohang University of Science and Technology, Pohang, Korea (M.K., D.H.); Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea (M.K.); and Department of new Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea (D.H.).
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.affiliation: From the Department of Biochemistry, College of Life Science and Biotechnology (J.K., Y.J., W.-b.L., H.P., Y.-G.K.) and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine (J.-Y.K.), Yonsei University, Seoul, Korea; School of Interdisciplinary Biosciences and Bioengineering, Pohang University of Science and Technology, Pohang, Korea (M.K., D.H.); Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea (M.K.); and Department of new Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea (D.H.).
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: From the Department of Biochemistry, College of Life Science and Biotechnology (J.K., Y.J., W.-b.L., H.P., Y.-G.K.) and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine (J.-Y.K.), Yonsei University, Seoul, Korea; School of Interdisciplinary Biosciences and Bioengineering, Pohang University of Science and Technology, Pohang, Korea (M.K., D.H.); Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea (M.K.); and Department of new Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea (D.H.). ygkwon@yonsei.ac.kr.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
mesh_terms: D030201:Activin Receptors, Type I / Q000096:biosynthesis / Q000235:genetics*; D030301:Activin Receptors, Type II; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D005312:Fetal Blood / Q000166:cytology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D055427:Growth Differentiation Factor 2 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007511:Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000097:blood / Q000235:genetics* / Q000473:pathology; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D012313:RNA; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse
keywords: activin receptors; endothelial cells; endothelial progenitor cells; growth differentiation factor 2; ischemia; neovascularization, pathologic