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.

Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1

“…In particular, phosphorylation of Ser240-244 of S6, a specific target of the AKT-mTOR pathway, is downregulated in CDKL5 mutants, a feature also shared by RTT models carrying MeCP2 deletion (3,11,31). IGF-1 is a potential activator of this pathway (18,32,33) and treatment with IGF-1 improves organism function, specific behaviors, cellular pathway activation, and synaptic plasticity in mice model of RTT syndrome (19,34) and Phelan-McDermid syndrome, a syndrome caused by mutations of PSD-95 binding protein Shank-3 (35). In particular, MeCP2 mutant mice were found to have an impaired spine motility and formation (22,36).…”

IGF-1/IGF-1R/hsa-let-7c axis regulates the committed differentiation of stem cells from apical papilla

“…The activated IGF-1R can combine corresponding molecules to trigger the downstream signaling cascades including MAPK pathway, thereby regulating the cell transformation, growth and survival4849. In particular, IGF-1R and p38 MAPK pathway can control the quiescence of hDPSCs and will be inactivated when DPSCs mitosis occurs50. As the upstream regulators of MAPK pathway, IGF-1R and let-7 work closely as a whole in cell differentiation.…”

IGFBP-2 and -3 co-ordinately regulate IGF1 induced matrix mineralisation of differentiating human dental pulp cells

“…Although IGF1 has been reported previously to promote the differentiation of human dental pulp stem cells via mTor (Feng et al, 2014) and MAPK/Stat-3 (Vandomme et al, 2014) signalling pathways there is only a limited literature describing IGFBP-2 and/or IGFBP-3 expression and activity during osteogenic differentiation. A direct effect of IGFBP-2 on the osteoblastic differentiation of rat calvarial cells via a receptor tyrosine phosphatase β (RPTPβ) based mechanism was recently reported (Xi et al, 2014).…”