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      bFGF stimulated plasminogen activation factors, but inhibited alkaline phosphatase and SPARC in stem cells from apical Papilla: Involvement of MEK/ERK, TAK1 and p38 signaling

      a , b , c , d , e , f , g , c , d , h , b , c , d , * , c , d , e , f , *
      Journal of Advanced Research
      Basic fibroblast growth factor, Matrix turnover, Plasminogen activation system, Signal transduction, Stem cells from apical papilla, Akt, protein kinase B, ALP, alkaline phosphatase, BAC, β-actin, bFGF, basic fibroblast growth factor, BSA, bovine serum albumin, DAPI, 4′,6-diamidino-2-phenylindole, DMSO, dimethylsulfoxide, ELISA, enzyme-linked immunosorbent assay, ERK, extracellular signal-regulated kinase, FBS, fetal bovine serum, FGFR, fibroblast growth factor receptor, IGF-1, insulin-like growth factor-1, MEK, mitogen-activated protein kinase kinase, MSCs, mesenchymal stem cells, MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Osx, osterix, PAI-1, plasminogen activator inhibitor-1, PBS, phosphate-buffered saline, PCR, polymerase chain reaction, PDGF, platelet-derived growth factor, PDL, periodontal ligament, PI3k, phosphatidylinositol-4,5-bisphosphate 3-kinase SB203580 4-(4-fluorophenyl)-2- (4-methylsulfinylphenyl)-5- (4-pyridyl)-imidazole , SCAP, stem cells from apical papilla, SPARC, secreted protein acidic and rich in cysteine (osteonectin), STAT, leukemia inhibitory factor-signal transducers and activators of transcription, TAK1, TGF-α-activated kinase-1, TGF-α, transforming growth factor-α, TIMP-1, tissue inhibitor of metalloproteinase-1, U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene, uPA, urokinase plasminogen activator, uPAR, urokinase plasminogen activator receptor

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          Graphical abstract


          • bFGF induced uPA, uPAR, PAI-1 production/expression in SCAP →

          • bFGF induced decline of ALP and SPARC of SCAP →

          • The effects of bFGF are regulated by ERK, p38, TAK1 and Akt signaling →

          • Crucial for SCAP proliferation, matrix turnover and differentiation →

          • These events are important for revascularization/root apexogenesis



          Basic fibroblast growth factor (bFGF) plays a critical role in odontoblast differentiation and dentin matrix deposition, thereby aiding pulpo-dentin repair and regeneration.


          The purpose of this study was to clarify the effects of bFGF on plasminogen activation factors, TIMP-1), ALP; and SPARC (osteonectin) expression/production of stem cells from apical papilla (SCAP) in vitro; and the involvement of MEK/ERK, p38, Akt, and TAK1 signaling.


          SCAP were exposed to bFGF with/without pretreatment and co-incubation with various signal transduction inhibitors (U0126, SB203580, LY294002, and 5Z-7-oxozeaenol). The expression of FGF receptors (FGFRs), PAI-1, uPA, p-ERK, p-TAK1, and p-p38 was analyzed via immunofluorescent staining. The gene expression and protein secretion of SCAP were determined via real-time PCR and ELISA. ALP activity was evaluated via ALP staining.


          SCAP expressed FGFR1, 2, 3, and 4. bFGF stimulated the PAI-1, uPA, uPAR, and TIMP-1 mRNA expression (p < 0.05). bFGF induced PAI-1, uPA, and soluble uPAR production (p < 0.05) but suppressed the ALP activity and SPARC production (p < 0.05) of SCAP. bFGF stimulated ERK, TAK1, and p38 phosphorylation of SCAP. U0126 (a MEK/ERK inhibitor) and 5Z-7-oxozeaenol (a TAK1 inhibitor) attenuated the bFGF-induced PAI-1, uPA, uPAR, and TIMP-1 expression and production of SCAP, but SB203580 (a p38 inhibitor) did not. LY294002, SB203580, and 5Z-7oxozeaenol could not reverse the inhibition of ALP activity caused by bFGF. Interestingly, U0126 and 5Z-7-oxozeaenol prevented the bFGF-induced decline of SPARC production (p < 0.05).


          bFGF may regulate fibrinolysis and matrix turnover via modulation of PAI-1, uPA, uPAR, and TIMP-1, but bFGF inhibited the differentiation (ALP, SPARC) of SCAP. These events are mainly regulated by MEK/ERK, p38, and TAK1. Combined use of bFGF and SCAP may facilitate pulpal/root repair and regeneration via regulation of the plasminogen activation system, migration, matrix turnover, and differentiation of SCAP.

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          Most cited references57

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          Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: a pilot study.

          Mesenchymal stem cells (MSCs) have been isolated from the pulp tissue of permanent teeth (dental pulp stem cells or DPSCs) and deciduous teeth (stem cells from human exfoliated deciduous teeth). We recently discovered another type of MSCs in the apical papilla of human immature permanent teeth termed stem cells from the apical papilla (SCAP). Here, we further characterized the apical papilla tissue and stem cell properties of SCAP using histologic, immunohistochemical, and immunocytofluorescent analyses. We found that the apical papilla is distinctive to the pulp in terms of containing less cellular and vascular components than those in the pulp. Cells in the apical papilla proliferated 2- to 3-fold greater than those in the pulp in organ cultures. Both SCAP and DPSCs were as potent in osteo/dentinogenic differentiation as MSCs from bone marrows, whereas they were weaker in adipogenic potential. The immunophenotype of SCAP is similar to that of DPSCs on the osteo/dentinogenic and growth factor receptor gene profiles. Double-staining experiments showed that STRO-1 coexpressed with dentinogenic markers such as bone sialophosphoprotein, osteocalcin, and growth factors FGFR1 and TGFbetaRI in cultured SCAP. Additionally, SCAP express a wide variety of neurogenic markers such as nestin and neurofilament M upon stimulation with a neurogenic medium. We conclude that SCAP are similar to DPSCs but a distinct source of potent dental stem/progenitor cells. Their implications in root development and apexogenesis are discussed.
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            The hidden treasure in apical papilla: the potential role in pulp/dentin regeneration and bioroot engineering.

            Some clinical case reports have shown that immature permanent teeth with periradicular periodontitis or abscess can undergo apexogenesis after conservative endodontic treatment. A call for a paradigm shift and new protocol for the clinical management of these cases has been brought to attention. Concomitantly, a new population of mesenchymal stem cells residing in the apical papilla of permanent immature teeth recently has been discovered and was termed stem cells from the apical papilla (SCAP). These stem cells appear to be the source of odontoblasts that are responsible for the formation of root dentin. Conservation of these stem cells when treating immature teeth may allow continuous formation of the root to completion. This article reviews current findings on the isolation and characterization of these stem cells. The potential role of these stem cells in the following respects will be discussed: (1) their contribution in continued root maturation in endodontically treated immature teeth with periradicular periodontitis or abscess and (2) their potential utilization for pulp/dentin regeneration and bioroot engineering.
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              Is Open Access

              Protection of SH-SY5Y Neuronal Cells from Glutamate-Induced Apoptosis by 3,6′-Disinapoyl Sucrose, a Bioactive Compound Isolated from Radix Polygala

              The neuroprotective effects of 3,6′-disinapoyl sucrose (DISS) from Radix Polygala against glutamate-induced SH-SY5Y neuronal cells injury were evaluated in the present study. SH-SY5Y neuronal cells were pretreated with glutamate (8 mM) for 30 min followed by cotreatment with DISS for 12 h. Cell viability was determined by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide (MTT) assay, and apoptosis was confirmed by cell morphology and flow cytometry assay, evaluated with propidium iodide dye. Treatment with DISS (0.6, 6, and 60 μmol/L) increased cell viability dose dependently, inhibited LDH release, and attenuated apoptosis. The mechanisms by which DISS protected neuron cells from glutamate-induced excitotoxicity included the downregulation of proapoptotic gene Bax and the upregulation of antiapoptotic gene Bcl-2. The present findings indicated that DISS exerts neuroprotective effects against glutamate toxicity, which might be of importance and contribute to its clinical efficacy for the treatment of neurodegenerative diseases.

                Author and article information

                J Adv Res
                J Adv Res
                Journal of Advanced Research
                28 December 2021
                September 2022
                28 December 2021
                : 40
                : 95-107
                [a ]Biomedical Science Team, Chang Gung University of Science and Technology, Kwei-Shan, Taoyun City, Taiwan
                [b ]Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan
                [c ]Graduate Institute of Clinical Dentistry, National Taiwan University Medical College, Taiwan
                [d ]Department of Dentistry, National Taiwan University Hospital, Taiwan
                [e ]School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
                [f ]Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
                [g ]Department of Dentistry, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
                [h ]Department of Dentistry, Cardinal-Tien Hospital, New Taipei City, Taiwan
                Author notes
                [* ]Corresponding authors at: School of Dentistry and Department of Dentistry, National Taiwan University Medical College & National Taiwan University Hospital, No 1, Chang Te Street, Taipei, Taiwan (Jiiang-Huei Jeng). School of Dentistry, National Taiwan University Medical College, No 1, Chang Te Street, Taipei, Taiwan(Hsiao-Hua Chang). hhhchang@ 123456ntu.edu.tw jhjeng@ 123456ntu.edu.tw jhjeng@ 123456kmu.edu.tw
                © 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 6 October 2021
                : 4 December 2021
                : 14 December 2021
                Original Article

                basic fibroblast growth factor,matrix turnover,plasminogen activation system,signal transduction,stem cells from apical papilla,akt, protein kinase b,alp, alkaline phosphatase,bac, β-actin,bfgf, basic fibroblast growth factor,bsa, bovine serum albumin,dapi, 4′,6-diamidino-2-phenylindole,dmso, dimethylsulfoxide,elisa, enzyme-linked immunosorbent assay,erk, extracellular signal-regulated kinase,fbs, fetal bovine serum,fgfr, fibroblast growth factor receptor,igf-1, insulin-like growth factor-1,mek, mitogen-activated protein kinase kinase,mscs, mesenchymal stem cells,mtt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,osx, osterix,pai-1, plasminogen activator inhibitor-1,pbs, phosphate-buffered saline,pcr, polymerase chain reaction,pdgf, platelet-derived growth factor,pdl, periodontal ligament,pi3k, phosphatidylinositol-4,5-bisphosphate 3-kinase sb203580 4-(4-fluorophenyl)-2- (4-methylsulfinylphenyl)-5- (4-pyridyl)-imidazole,scap, stem cells from apical papilla,sparc, secreted protein acidic and rich in cysteine (osteonectin),stat, leukemia inhibitory factor-signal transducers and activators of transcription,tak1, tgf-α-activated kinase-1,tgf-α, transforming growth factor-α,timp-1, tissue inhibitor of metalloproteinase-1,u0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene,upa, urokinase plasminogen activator,upar, urokinase plasminogen activator receptor


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