title: Insulin-like growth factor 1 receptor and p38 mitogen-activated protein kinase signals inversely regulate signal transducer and activator of transcription 3 activity to control human dental pulp stem cell quiescence, propagation, and differentiation.
abstract: Dental pulp stem cells (DPSCs) remain quiescent until activated in response to severe dental pulp damage. Once activated, they exit quiescence and enter regenerative odontogenesis, producing reparative dentin. The factors and signaling molecules that control the quiescence/activation and commitment to differentiation of human DPSCs are not known. In this study, we determined that the inhibition of insulin-like growth factor 1 receptor (IGF-1R) and p38 mitogen-activated protein kinase (p38 MAPK) signaling commonly activates DPSCs and promotes their exit from the G0 phase of the cell cycle as well as from the pyronin Y(low) stem cell compartment. The inhibition of these two pathways, however, inversely determines DPSC fate. In contrast to p38 MAPK inhibitors, IGF-1R inhibitors enhance dental pulp cell sphere-forming capacity and reduce the cells' colony-forming capacity without inducing cell death. The inverse cellular changes initiated by IGF-1R and p38 MAPK inhibitors were accompanied by inverse changes in the levels of active signal transducer and activator of transcription 3 (STAT3) factor, inactive glycogen synthase kinase 3, and matrix extracellular phosphoglycoprotein, a marker of early odontoblast differentiation. Our data suggest that there is cross talk between the IGF-1R and p38 MAPK signaling pathways in DPSCs and that the signals provided by these pathways converge at STAT3 and inversely regulate its activity to maintain quiescence or to promote self-renewal and differentiation of the cells. We propose a working model that explains the possible interactions between IGF-1R and p38 MAPK at the molecular level and describes the cellular consequences of these interactions. This model may inspire further fundamental study and stimulate research on the clinical applications of DPSC in cellular therapy and tissue regeneration.
authors.affiliation: 1 Inserm U837 Jean-Pierre Aubert Research Center, Institut pour la Recherche sur le Cancer de Lille (IRCL) , Lille, France .
authors.forename: Jerome
authors.initials: J
authors.lastname: Vandomme
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Touil
authors.forename: Pauline
authors.initials: P
authors.lastname: Ostyn
authors.forename: Cecile
authors.initials: C
authors.lastname: Olejnik
authors.forename: Pilar
authors.initials: P
authors.lastname: Flamenco
authors.forename: Raja
authors.initials: R
authors.lastname: El Machhour
authors.forename: Pascaline
authors.initials: P
authors.lastname: Segard
authors.forename: Bernadette
authors.initials: B
authors.lastname: Masselot
authors.forename: Yves
authors.initials: Y
authors.lastname: Bailliez
authors.forename: Pierre
authors.initials: P
authors.lastname: Formstecher
authors.forename: Renata
authors.initials: R
authors.lastname: Polakowska
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003782:Dental Pulp / Q000166:cytology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007093:Imidazoles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017526:Receptor, IGF Type 1; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole