TY  - JOUR
AU  - Jeon, So Mi
AU  - Lim, Je Sun
AU  - Park, Su Hwan
AU  - Kim, Hyung Joon
AU  - Kim, Hyung-Ryong
AU  - Lee, Jong-Ho
PY  - 2022
TI  - Blockade of PD-L1/PD-1 signaling promotes osteo-/odontogenic differentiation through Ras activation
JO  - International Journal of Oral Science
SN  - 1674-2818
SP  - 18
VL  - 14
AB  - The programmed cell death ligand 1 (PD-L1) and its receptor programmed cell death 1 (PD-1) deliver inhibitory signals to regulate immunological tolerance during immune-mediated diseases. However, the role of PD-1 signaling and its blockade effect on human dental pulp stem cells (hDPSCs) differentiation into the osteo-/odontogenic lineage remain unknown. We show here that PD-L1 expression, but not PD-1, is downregulated during osteo-/odontogenic differentiation of hDPSCs. Importantly, PD-L1/PD-1 signaling has been shown to negatively regulate the osteo-/odontogenic differentiation of hDPSCs. Mechanistically, depletion of either PD-L1 or PD-1 expression increased ERK and AKT phosphorylation levels through the upregulation of Ras enzyme activity, which plays a pivotal role during hDPSCs osteo-/odontogenic differentiation. Treatment with nivolumab (a human anti-PD-1 monoclonal antibody), which targets PD-1 to prevent PD-L1 binding, successfully enhanced osteo-/odontogenic differentiation of hDPSCs through enhanced Ras activity-mediated phosphorylation of ERK and AKT. Our findings underscore that downregulation of PD-L1 expression accompanies during osteo-/odontogenic differentiation, and hDPSCs-intrinsic PD-1 signaling inhibits osteo-/odontogenic differentiation. These findings provide a significant basis that PD-1 blockade could be effective immunotherapeutic strategies in hDPSCs-mediated dental pulp regeneration.
UR  - https://doi.org/10.1038/s41368-022-00168-2
DO  - 10.1038/s41368-022-00168-2