LPAR2 Inhibition Expedites Odontoblastic Differentiation of Dental Pulp Stem Cells

Objectives: Previous studies have shown the relation of lysophosphatidic acid (LPA) signaling regulates with the self-renewal and differentiation of various stem cells. However, the effect of LPA signaling on dental stem cells has not been reported. We investigate the role of LPA signaling in the regulation of dental pulp stem cells (DPSCs).
Methods: DPSCs were cultured in the maintenance media and subjected to osteogenic differentiation. To modulate LPAR activity, various LPAR-inhibiting or activating chemicals were applied during maintenance culture or osteogenic differentiation. Selected chemicals were progressed to DPSC differentiation in vitro and dentin regeneration in vivo.
Results: Among LPA receptor inhibitors, LPAR2 inhibitor promoted the proliferation of DPSCs in the maintenance culture but inhibited the proliferation during osteogenic differentiation culture. When DPSCs were treated with different concentration of LPAR2 inhibitor during osteogenic differentiation, increasing dose of LPAR2 inhibitor accelerated osteogenic differentiation, in which the differentiation period was reduced from three weeks to one week with the increase in the expression of DSPP, DMP-1, RUNX2, Osteopontin and the decrease in LPAR2 expression. Electron microscope analysis showed the LPAR2 inhibitor-treated DPSCs exhibited the odontoblast morphology with elongated progress, polar localization of nucleus and development of organelles related to secretion. Application of LPAR2 inhibitor to molar cavity in mouse model showed the regeneration of dental pulp and dentin.
Conclusions: These results suggest that the inhibition of LPAR2 signaling positively regulates the proliferation and odontogenic maturation of DPSCs, which may contribute to the development of the regenerative medicine in dentistry.