title: The secretome of endothelial progenitor cells promotes brain endothelial cell activity through PI3-kinase and MAP-kinase.
abstract: BACKGROUND
  Angiogenesis and vascular remodelling are crucial events in tissue repair mechanisms promoted by cell transplantation. Current evidence underscores the importance of the soluble factors secreted by stem cells in tissue regeneration. In the present study we investigated the effects of paracrine factors derived from cultured endothelial progenitor cells (EPC) on rat brain endothelial cell properties and addressed the signaling pathways involved.
  
  
  METHODS
  Endothelial cells derived from rat brain (rBCEC4) were incubated with EPC-derived conditioned medium (EPC-CM). The angiogenic response of rBCEC4 to EPC-CM was assessed as effect on cell number, migration and tubular network formation. In addition, we have compared the outcome of the in vitro experiments with the effects on capillary sprouting from rat aortic rings. The specific PI3K/AKT inhibitor LY294002 and the MEK/ERK inhibitor PD98059 were used to study the involvement of these two signaling pathways in the transduction of the angiogenic effects of EPC-CM.
  
  
  RESULTS
  Viable cell number, migration and tubule network formation were significantly augmented upon incubation with EPC-CM. Similar findings were observed for aortic ring outgrowth with significantly longer sprouts. The EPC-CM-induced activities were significantly reduced by the blockage of the PI3K/AKT and MEK/ERK signaling pathways. Similarly to the outcome of the rBCEC4 experiments, inhibition of the PI3K/AKT and MEK/ERK pathways significantly interfered with capillary sprouting induced by EPC-CM.
  
  
  CONCLUSIONS
  The present study demonstrates that EPC-derived paracrine factors substantially promote the angiogenic response of brain microvascular endothelial cells. In addition, our findings identified the PI3K/AKT and MEK/ERK pathways to play a central role in mediating these effects.
authors.affiliation: Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, University of Bern, Inselspital, Bern, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Santo
authors.affiliation: Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, University of Bern, Inselspital, Bern, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Seiler
authors.affiliation: Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, University of Bern, Inselspital, Bern, Switzerland.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Fuchs
authors.affiliation: Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, University of Bern, Inselspital, Bern, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Staudigl
authors.affiliation: Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, University of Bern, Inselspital, Bern, Switzerland.
authors.forename: Hans Rudolf
authors.initials: HR
authors.lastname: Widmer
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D066026:Endothelial Progenitor Cells / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing
chemical_list: D043925:Angiogenesis Inducing Agents; D017077:Culture Media, Conditioned; D016207:Cytokines; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
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