Department of Health Sciences, The Graduate School of Dong-A University, Busan, Republic of Korea.
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.
Int J Oral Sci. 2022 Apr 1;14(1):18. doi: 10.1038/s41368-022-00168-2.
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.
程序性细胞死亡配体 1（PD-L1）及其受体程序性细胞死亡蛋白 1（PD-1）在免疫介导的疾病中传递抑制信号以调节免疫耐受。然而，PD-1 信号及其对人牙髓干细胞（hDPSCs）向成骨/成牙本质谱系分化的阻断作用的作用尚不清楚。我们在这里表明，PD-L1 的表达而非 PD-1 在 hDPSCs 的成骨/成牙本质分化过程中下调。重要的是，PD-L1/PD-1 信号通路被证明可负调控 hDPSCs 的成骨/成牙本质分化。从机制上讲，通过 Ras 酶活性的上调，耗尽 PD-L1 或 PD-1 的表达可增加 ERK 和 AKT 的磷酸化水平，这在 hDPSCs 的成骨/成牙本质分化中起着关键作用。用 nivolumab（一种人抗 PD-1 单克隆抗体）处理，该抗体可靶向 PD-1 以防止 PD-L1 结合，通过增强 Ras 活性介导的 ERK 和 AKT 的磷酸化，成功增强了 hDPSCs 的成骨/成牙本质分化。我们的研究结果表明，PD-L1 表达的下调伴随着成骨/成牙本质分化，而 hDPSCs 内在的 PD-1 信号抑制成骨/成牙本质分化。这些发现为 PD-1 阻断可能成为 hDPSCs 介导的牙髓再生的有效免疫治疗策略提供了重要依据。
