Combination of three angiogenic growth factors has synergistic effects on sprouting of endothelial cell/mesenchymal stem cell-based spheroids in a 3D matrix.
Combinations of angiogenic growth factors have been shown to have synergistic effects on angiogenesis and natural wound healing in various animal models. Each growth factor has unique roles during angiogenesis; vascular endothelial growth factor (VEGF) plays a key role during the initial step of angiogenesis, whereas PDGF functions in the maturation of blood vessels. We used a combination of three angiogenic growth factors to increase angiogenesis in vitro and in vivo. We chose VEGF as a basic factor and added platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) to induce angiogenesis in three in vitro and in vivo models: 3D angiogenesis assay, 3D co-culture, and matrigel plug implantation assay. Cell proliferation was significantly higher in co-cultured cells treated with PDGF + VEGF + FGF than in the control, single, or dual combination groups. mRNA expression of α-smooth muscle actin (α-SMA), von Willebrand factor (vWF), and CD105 was higher in the triple group (PDGF + VEGF + FGF) than in control, single, or dual combination groups. In the PDGF + VEGF + FGF group, the length and number of branches of spheroids was also significantly higher than in the control, single, or dual combination groups. Furthermore, in a nude mouse model, α-SMA expression was significantly higher in the PDGF + VEGF + FGF group than in other groups. In conclusion, the addition of PDGF and FGF to VEGF showed synergistic effects on angiogenesis in vitro and in vivo. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1535-1543, 2016.
Department of Biomedical Engineering, Medical College, Korea University, Seoul, Korea.
Sook Kyoung
SK
Kim
Department of Biomedical Engineering, Medical College, Korea University, Seoul, Korea.
Jaeyeon
J
Lee
Department of Biomedical Engineering, Medical College, Korea University, Seoul, Korea.
Myeongjin
M
Song
Department of Biomedical Engineering, Medical College, Korea University, Seoul, Korea.
Mirim
M
Kim
Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital, School of Dentistry, Dental Research Institute, BK 21 Plus, Korea.
Soon Jung
SJ
Hwang
Department of Biomedical Engineering, Medical College, Korea University, Seoul, Korea.
Hwanseok
H
Jang
Department of Biomedical Engineering, Medical College, Korea University, Seoul, Korea. ydpark@kumc.or.kr.
Yongdoo
Y
Park
D000818:Animals; D005109:Extracellular Matrix / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000494:pharmacology
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
angiogenesis/neovasculization; growth factor; matrix