Blockade of PD-L1/PD-1 signaling promotes osteo-/odontogenic differentiation through Ras activation.
10.1038/s41368-022-00168-2
- Author:
So Mi JEON
1
;
Je Sun LIM
1
;
Su Hwan PARK
1
;
Hyung Joon KIM
2
;
Hyung-Ryong KIM
3
;
Jong-Ho LEE
4
Author Information
1. Department of Health Sciences, The Graduate School of Dong-A University, Busan, Republic of Korea.
2. Department of Oral Physiology, Periodontal Diseases Signaling Network Research Center, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Republic of Korea.
3. Department of Pharmacology, College of Dentistry, Jeonbuk National University, Jeonju, Republic of Korea. hrkimdp@gmail.com.
4. Department of Health Sciences, The Graduate School of Dong-A University, Busan, Republic of Korea. Topljh19@dau.ac.kr.
- Publication Type:Journal Article
- MeSH:
B7-H1 Antigen/metabolism*;
Dental Pulp/metabolism*;
Humans;
Programmed Cell Death 1 Receptor/metabolism*;
Regeneration;
Stem Cells
- From:
International Journal of Oral Science
2022;14(1):18-18
- CountryChina
- Language:English
-
Abstract:
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.
