title: Notch1 signalling inhibits apoptosis of human dental follicle stem cells via both the cytoplasmic mitochondrial pathway and nuclear transcription regulation.
abstract: Dental follicle stem cells (DFSCs) have been considered as promising candidate cells for periodontal tissue regeneration. Understanding the signalling pathways underlying the apoptosis of DFSCs will facilitate its biomedical application. Here we showed that Notch1 signalling could inhibit DFSCs apoptosis because the constitutive overexpression of the intracellular domain of Notch1 (ICN1) promoted proliferation and suppressed apoptosis by inhibiting cytoplasmic mitochondrial membrane depolarization, cytochrome c release and activation of caspase-9 and caspase-3. The survival-promoting effect of Notch1 was also accomplished by up-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1, down-regulation of the pro-apoptotic proteins Bax and Bad, and blockade of Bax multimerization. Moreover, p-Akt (S473) was significantly increased after ectopic Notch 1 activation. The expression of p53 was also inhibited in Notch1-overexpressing DFSCs, while the ectopic expression of p53 promoted apoptosis even when Notch1 was overexpressed. Meanwhile, all of the opposite phenomena were observed in Notch1 shRNA-silenced DFSCs. Our data strongly suggested that Notch1 signalling inhibited the apoptosis of DFSCs via the cytoplasmic mitochondrial pathway and ICN-Akt signalling pathway, together with nuclear gene expression regulation. These findings would provide molecular cues for the further medical application of DFSCs.
authors.affiliation: Department of Orthodontics, Hospital of Stomatology, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: cxp1979@163.com.
authors.forename: Xuepeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Oral Pathology, Hospital of Stomatology, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Songying
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Stomatology, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China.
authors.forename: Zhaobin
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Orthodontics, Qindu Stomatological College, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Zexu
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Orthodontics, Hospital of Stomatology, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Orthodontics, Hospital of Stomatology, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Department of Oral Implantology, Hospital of Stomatology, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Oral Pathology, Hospital of Stomatology, Zhejiang University, Hangzhou, Zhejiang, China; Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: hmwang1960@hotmail.com.
authors.forename: Huiming
authors.initials: H
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003795:Dental Sac / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D008297:Male; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C497761:NOTCH1 protein, human; D010446:Peptide Fragments; D051881:Receptor, Notch1; D011994:Recombinant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Apoptosis; Dental follicle stem cell; Gene expression; Mitochondrial pathway; Notch signalling