title: EphB4 Regulates Self-Renewal, Proliferation and Neuronal Differentiation of Human Embryonic Neural Stem Cells in Vitro.
abstract: OBJECTIVE
  EphB4 belongs to the largest family of Eph receptor tyrosine kinases. It contributes to a variety of pathological progresses of cancer malignancy. However, little is known about its role in neural stem cells (NSCs). This study examined whether EphB4 is required for proliferation and differentiation of human embryonic neural stem cells (hNSCs) in vitro.
  
  
  METHODS
  We up- and down-regulated EphB4 expression in hNSCs using lentiviral over-expression and shRNA knockdown constructs and then investigated the influence of EphB4 on the properties of hNSCs.
  
  
  RESULTS
  Our results show that shRNA-mediated EphB4 reduction profoundly impaired hNSCs self-renewal and proliferation. Furthermore, detection of differentiation revealed that knockdown of EphB4 inhibited hNSCs differentiation towards a neuronal lineage and promoted hNSCs differentiation to glial cells. In contrast, EphB4 overexpression promoted hNSCs self-renewal and proliferation, further induced hNSCs differentiation towards a neuronal lineage and inhibited hNSCs differentiation to glial cells. Moreover, we found that EphB4 regulates cell proliferation mediated by the Abl-CyclinD1 pathway.
  
  
  CONCLUSIONS
  These studies provide strong evidence that fine tuning of EphB4 expression is crucial for the proliferation and neuronal differentiation of hNSCs, suggesting that EphB4 might be an interesting target for overcoming some of the therapeutic limitations of neuronal loss in brain diseases.
authors.forename: Tingting
authors.initials: T
authors.lastname: Liu
authors.forename: Xianwei
authors.initials: X
authors.lastname: Zeng
authors.forename: Fangling
authors.initials: F
authors.lastname: Sun
authors.forename: Hongli
authors.initials: H
authors.lastname: Hou
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Guan
authors.forename: Deyu
authors.initials: D
authors.lastname: Guo
authors.forename: Houxi
authors.initials: H
authors.lastname: Ai
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Guojun
authors.initials: G
authors.lastname: Zhang
mesh_terms: D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D006801:Humans; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D034741:RNA, Small Interfering; D019938:Cyclin D1; D036224:Receptor, EphB4; D016315:Proto-Oncogene Proteins c-abl; D051358:Cyclin-Dependent Kinase 4
keywords: Differentiation; EphB4 signaling; Neural stem cells; Neuron; Proliferation; Self-renewal