title: COMP-Ang1 Potentiates EPC Treatment of Ischemic Brain Injury by Enhancing Angiogenesis Through Activating AKT-mTOR Pathway and Promoting Vascular Migration Through Activating Tie2-FAK Pathway.
abstract: Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2-FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins ανβ3, α4, β1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1α to induce angiogenesis. Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.
authors: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors: Hyo Eun
authors: HE
authors: Moon
authors: Center for Regenerative Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea. ; Department of Anatomy and Cell Biology, Gachon University Medical School, Incheon 406-840, Korea.
authors: Kyunghee
authors: K
authors: Byun
authors: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors: Hyung Woo
authors: HW
authors: Park
authors: Clinical Research Institute, Gyeongsang National University Hospital, Jinju 660-702, Korea.
authors: Jin Hyun
authors: JH
authors: Kim
authors: Innovative Research Institute for Cell Therapy (IRICT), Seoul National University Hospital, Seoul 110-744, Korea.
authors: Jin
authors: J
authors: Hur
authors: Department of Obstetrics & Gynecology, Seoul National University Hospital, Seoul 110-744, Korea.
authors: Joong Shin
authors: JS
authors: Park
authors: Department of Obstetrics & Gynecology, Seoul National University Hospital, Seoul 110-744, Korea.
authors: Jong Kwan
authors: JK
authors: Jun
authors: Innovative Research Institute for Cell Therapy (IRICT), Seoul National University Hospital, Seoul 110-744, Korea.
authors: Hyo-Soo
authors: HS
authors: Kim
authors: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Department of Neurosurgery, Mayo Clinic, USA.
authors: Seung Leal
authors: SL
authors: Paek
authors: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors: In Keyoung
authors: IK
authors: Kim
authors: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors: Jae Ha
authors: JH
authors: Hwang
authors: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors: Jin Wook
authors: JW
authors: Kim
authors: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors: Dong Gyu
authors: DG
authors: Kim
authors: Division of Molecular and Life Science, Integrative Bioscience & Biotechnology, Pohang University of Science and Technology, Pohang 790-784, USA.
authors: Young Chul
authors: YC
authors: Sung
authors: Laboratory for Vascular Biology and Stem Cell, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-338, Korea.
authors: Gou-Young
authors: GY
authors: Koh
authors: Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, Minneapolis, USA.
authors: Chang W
authors: CW
authors: Song
authors: Center for Regenerative Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea. ; Department of Anatomy and Cell Biology, Gachon University Medical School, Incheon 406-840, Korea.
authors: Bonghee
authors: B
authors: Lee
authors: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors: Sun Ha
authors: SH
authors: Paek
keywords: COMP-Ang1; Tie2-FAK-AKT pathway; angiogenesis; ischemia