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.
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.
Exp Neurobiol. 2015 Mar;24(1):55-70. doi: 10.5607/en.2015.24.1.55. Epub 2015 Mar 13.
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.
由于缺血区周围的血管化不良，脑缺血的恢复是有限的。具有强大血管生成因子的细胞治疗可能是拯救缺血性大脑的有效策略。我们研究了软骨寡聚基质蛋白（COMP）-Ang1，一种可溶性、稳定且有效的 Ang1 变体，是否能增强人脐带来源内皮祖细胞（hCB-EPC）的血管生成能力，从而拯救脑缺血损伤。COMP-Ang1 显著改善了 EPC 形成毛细血管的管腔形成，并且在体外在 Matrigel 上孵育时，将 EPC 与人脐静脉内皮细胞（HUVEC）整合到管腔形成中。在划痕迁移实验中，COMP-Ang1 比 HUVEC 更能刺激 EPC 的迁移。移植的 EPC 和 COMP-Ang1 整合到血管中，减少了大鼠缺血性脑梗死体积。分子研究表明，COMP-Ang1 诱导 Tie2 和 FAK 之间的相互作用，但在 EPC 质膜中，AKT 与 Tie2-FAK-AKT 复合物分离。Tie2-FAK 增加了 pp38、pSAPK/JNK 和 pERK 介导的 MAPK 激活，并与整合素 ανβ3、α4、β1 相互作用，最终导致 EPC 迁移。AKT 招募 mTOR、SDF-1 和 HIF-1α 诱导血管生成。综上所述，结论是 COMP-Ang1 增强了 EPC 的血管生成能力，并增强了血管形态发生，表明 EPC 与 COMP-Ang1 的联合可能是缺血性脑损伤挽救治疗的一种潜在有效方案。
