Blockade of PD-L1/PD-1 signaling promotes osteo-/odontogenic differentiation through Ras activation.
Blockade of PD-L1/PD-1 signaling promotes osteo-/odontogenic differentiation through Ras activation.
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DOI：
10.1038/s41368-022-00168-2
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发表时间：
2022-04-01
影响因子：
14.9
通讯作者：
Lee JH
中科院分区：
文献类型：
--
作者：
Jeon SM;Lim JS;Park SH;Kim HJ;Kim HR;Lee JH
程序性细胞死亡配体1（PD-L1）及其受体程序性细胞死亡1（PD-1）在免疫介导的疾病期间传递抑制信号以调节免疫耐受。然而，PD-1信号传导的作用及其对人牙髓干细胞（hDPSC）分化为成骨/牙源性谱系的阻断作用仍然未知。我们发现PD-L1的表达在hDPSCs的成骨/成牙分化过程中下调，而PD-1的表达没有下调。重要的是，PD-L1/PD-1信号传导已显示负调节hDPSC的成骨/成牙分化。从机制上讲，PD-L1或PD-1表达的缺失通过Ras酶活性的上调增加了ERK和AKT磷酸化水平，Ras酶活性在hDPSC成骨/成牙分化过程中起着关键作用。nivolumab（一种人抗PD-1单克隆抗体）靶向PD-1以防止PD-L1结合，通过增强Ras活性介导的ERK和AKT磷酸化，成功增强了hDPSC的成骨/成牙分化。我们的研究结果强调了PD-L1表达的下调伴随着成骨/成牙分化，hDPSC内在的PD-1信号传导抑制了成骨/成牙分化。这些发现为PD-1阻断可能是hDPSCs介导的牙髓再生的有效免疫策略提供了重要依据。
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.
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PD-1和PD-L1检查点信号传导抑制癌症免疫疗法：机制，组合和临床结果。
影响因子：
5.6
作者：
Alsaab HO;Sau S;Alzhrani R;Tatiparti K;Bhise K;Kashaw SK;Iyer AK
通讯作者：
Iyer AK
影响因子：
7.2
作者：
Du S;McCall N;Park K;Guan Q;Fontina P;Ertel A;Zhan T;Dicker AP;Lu B
通讯作者：
Lu B
DOI：
10.1016/j.bbrc.2021.01.059
发表时间：
2021-01-29
影响因子：
3.1
作者：
Jeon, So Mi;Lim, Je Sun;Lee, Jong-Ho
通讯作者：
Lee, Jong-Ho
影响因子：
16.6
作者：
Bunda S;Burrell K;Heir P;Zeng L;Alamsahebpour A;Kano Y;Raught B;Zhang ZY;Zadeh G;Ohh M
通讯作者：
Ohh M
影响因子：
7.3
作者：
Patsoukis N;Brown J;Petkova V;Liu F;Li L;Boussiotis VA
通讯作者：
Boussiotis VA