title: Glucagon like peptide-1-directed human embryonic stem cells differentiation into insulin-producing cells via hedgehog, cAMP, and PI3K pathways.
abstract: OBJECTIVE
  That glucagonlike peptide-1 (GLP-1) induces differentiation of primate embryonic stem (ES) cells into insulin-producing cells has been reported by several groups and also confirmed with our observations.
  
  
  METHODS
  To further elucidate the process in detail and the signaling pathways involved in this differentiation, we induced human ES cells HUES1 differentiated into insulin secretion cells by GLP-1 treatment.
  
  
  RESULTS
  A time-dependent pattern of down expression of the stem cell markers (human telomerase reverse transcriptase and octamer-4), and the appearance of multiple beta-cell-specific proteins (insulin, glucokinase, glucose transporter, type 2, and islet duodenal homeobox 1) and hedgehog signal molecules (Indian hedgehog, sonic hedgehog, and hedgehog receptor, patched) have been identified. Cotreatment with hedgehog signal inhibitor cytopamine was able to block this differentiation, providing evidence of the involvement of the hedgehog signaling pathway in GLP-1-induced differentiation. We also observed increased transcripts of the transcription factors of activator protein 1, serum response element-1, DNA-binding transcription factors, and cAMP response element in GLP-1-induced ES cell differentiation. Inhibition profile by its specific inhibitors indicated that the cyclic adenosine monophosphate and phosphatidylinositol-3-kinase pathways, but not the mitogen-activated protein kinase pathway, were required for the induced differentiation of ES cells.
  
  
  CONCLUSIONS
  These data support that GLP-1 directs human ES cell differentiation into insulin-producing cells via hedgehog, cyclic adenosine monophosphate, and phosphatidylinositol-3-kinase pathways.
authors.affiliation: UCLA Center of Excellence in Pancreatic Disease, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024-7073, USA. huihongx@gmail.com
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Hui
authors.forename: Yongming G
authors.initials: YG
authors.lastname: Tang
authors.forename: Lunjian
authors.initials: L
authors.lastname: Zhu
authors.forename: Nasif
authors.initials: N
authors.lastname: Khoury
authors.forename: Zhe
authors.initials: Z
authors.lastname: Hui
authors.forename: Kevin Yuqi
authors.initials: KY
authors.lastname: Wang
authors.forename: Ricardo
authors.initials: R
authors.lastname: Perfetti
authors.forename: Vay Liang W
authors.initials: VL
authors.lastname: Go
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D050814:Octamer Transcription Factor-3 / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D012194:RNA-Directed DNA Polymerase / Q000502:physiology; D019098:Telomerase / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; D050814:Octamer Transcription Factor-3; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D012194:RNA-Directed DNA Polymerase; D019098:Telomerase