Upregulation of Flk-1 by bFGF via the ERK pathway is essential for VEGF-mediated promotion of neural stem cell proliferation.
Neural stem cells (NSCs) constitute the cellular basis for embryonic brain development and neurogenesis. The process is regulated by NSC niche including neighbor cells such as vascular and glial cells. Since both vascular and glial cells secrete vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), we assessed the effect of VEGF and bFGF on NSC proliferation using nearly homogeneous NSCs that were differentiated from mouse embryonic stem cells. VEGF alone did not have any significant effect. When bFGF was added, however, VEGF stimulated NSC proliferation in a dose-dependent manner, and this stimulation was inhibited by ZM323881, a VEGF receptor (Flk-1)-specific inhibitor. Interestingly, ZM323881 also inhibited cell proliferation in the absence of exogenous VEGF, suggesting that VEGF autocrine plays a role in the proliferation of NSCs. The stimulatory effect of VEGF on NSC proliferation depends on bFGF, which is likely due to the fact that expression of Flk-1 was upregulated by bFGF via phosphorylation of ERK1/2. Collectively, this study may provide insight into the mechanisms by which microenvironmental niche signals regulate NSCs.
Xiao
Zhifeng
Z
Peking University Stem Cell Research Center and Cell Biology Department, Peking University Health Science Center, Beijing, China.
Kong
Yaxian
Y
Yang
Shufa
S
Li
Meiyu
M
Wen
Jinhua
J
Li
Lingsong
L
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000502:physiology; D009474:Neurons / Q000166:cytology*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases