title: Infantile hemangioma-derived stem cells and endothelial cells are inhibited by class 3 semaphorins.
abstract: Class 3 semaphorins were discovered as a family of axon guidance molecules, but are now known to be involved in diverse biologic processes. In this study, we investigated the anti-angiogenic potential of SEMA3E and SEMA3F (SEMA3E&F) in infantile hemangioma (IH). IH is a common vascular tumor that involves both vasculogenesis and angiogenesis. Our lab has identified and isolated hemangioma stem cells (HemSC), glucose transporter 1 positive (GLUT1(+)) endothelial cells (designated as GLUT1(sel) cells) based on anti-GLUT1 magnetic beads selection and GLUT1-negative endothelial cells (named HemEC). We have shown that these types of cells play important roles in hemangiogenesis. We report here that SEMA3E inhibited HemEC migration and proliferation while SEMA3F was able to suppress the migration and proliferation in all three types of cells. Confocal microscopy showed that stress fibers in HemEC were reduced by SEMA3E&F and that stress fibers in HemSC were decreased by SEMA3F, which led to cytoskeletal collapse and loss of cell motility in both cell types. Additionally, SEMA3E&F were able to inhibit vascular endothelial growth factor (VEGF)-induced sprouts in all three types of cells. Further, SEMA3E&F reduced the level of p-VEGFR2 and its downstream p-ERK in HemEC. These results demonstrate that SEMA3E&F inhibit IH cell proliferation and suppress the angiogenic activities of migration and sprout formation. SEMA3E&F may have therapeutic potential to treat or prevent growth of highly proliferative IH.
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Ehime 791-0295, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Kelly
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Clara R L
authors.initials: CR
authors.lastname: Oudenaarden
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Adelle
authors.initials: A
authors.lastname: Dagher
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Hofmann
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marsha A
authors.initials: MA
authors.lastname: Moses
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: joyce.bischoff@childrens.harvard.edu.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: michael.klagsbrun@childrens.harvard.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Klagsbrun
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006391:Hemangioma / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D006801:Humans; D007223:Infant; D008565:Membrane Proteins / Q000494:pharmacology*; D009383:Neoplasms, Vascular Tissue / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D039961:Semaphorins / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C494123:SEMA3E protein, human; C491230:SEMA3F protein, human; D039961:Semaphorins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Endothelial cell; Facultative stem cell; Infantile hemangioma; MAPK; Plexin; Semaphorin