title: Inhibition of Notch Signaling Promotes the Adipogenic Differentiation of Mesenchymal Stem Cells Through Autophagy Activation and PTEN-PI3K/AKT/mTOR Pathway.
abstract: BACKGROUND
  The Notch signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. This study was designed to determine the role of Notch signaling in adipogenic differentiation of human bone marrow derived MSCs (BM-MSCs).
  
  
  METHODS
  The Notch signaling was inhibited by the γ-secretase inhibitor N-[N-(3,5-difluor- ophenacetyl-L-alanyl)]-S-phenylglycine t-butylester (DAPT). The markers involving adipogenic differentiation of MSCs, the relative pathway PTEN-PI3K/Akt/mTOR and autophagy activation were then analyzed. Furthermore, the autophagy inhibitor chloroquine (CQ) and 3-methyladenine (3-MA) were used to study the role of autophagy in the DAPT-induced the adipogenic differentiation of MSCs.
  
  
  RESULTS
  We first confirmed the down -regulation of Notch gene expression during MSCs adipocyte differentiation, and showed that the inhibition of Notch signaling significantly enhanced adipogenic differentiation of MSCs. Furthermore, Notch inhibitor DAPT induced early autophagy by acting on PTEN-PI3K/Akt/mTOR pathway. The autophagy inhibitor CQ and 3-MA dramatically abolished the effects of DAPT-induced autophagy and adipogenic differentiation of MSCs.
  
  
  CONCLUSIONS
  Our results indicate that inhibition of Notch signaling could promote MSCs adipogenesis mediated by autophagy involving PTEN-PI3K/Akt/mTOR pathway. Notch signaling could be a novel target for regulating the adipogenic differentiation of MSCs.
authors.affiliation: State Key Laboratory of Experimental Hematology, National Engineering Research Center of Stem Cells, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
authors.forename: Bao-quan
authors.initials: BQ
authors.lastname: Song
authors.forename: Ying
authors.initials: Y
authors.lastname: Chi
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.forename: Wen-jing
authors.initials: WJ
authors.lastname: Du
authors.forename: Zhi-Bo
authors.initials: ZB
authors.lastname: Han
authors.forename: Jian-jian
authors.initials: JJ
authors.lastname: Tian
authors.forename: Juan-juan
authors.initials: JJ
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.forename: He-he
authors.initials: HH
authors.lastname: Wu
authors.forename: Li-xin
authors.initials: LX
authors.lastname: Han
authors.forename: Shi-hong
authors.initials: SH
authors.lastname: Lu
authors.forename: Yi-zhou
authors.initials: YZ
authors.lastname: Zheng
authors.forename: Zhong-chao
authors.initials: ZC
authors.lastname: Han
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D001343:Autophagy; D002454:Cell Differentiation; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D004151:Dipeptides; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051880:Receptors, Notch; D058570:TOR Serine-Threonine Kinases; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C546842:MTOR protein, human; C494929:PTEN protein, human