Zhang Ye, Lian Min, Zhao Xin, Cao Peipei, Xiao Jingwen, Shen Shuling, Tang Wanxian, Zhang Jiaxuan, Hao Jie, Feng Xingmei
Jiangsu Vocational College of Medicine, Yancheng, China.
Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, China.
Cell Biol Int. 2021 Mar;45(3):569-579. doi: 10.1002/cbin.11498. Epub 2021 Jan 25.
Dental pulp stem cells (DPSCs) are capable of both self-renewal and multilineage differentiation, which play a positive role in dentinogenesis. Studies have shown that tumor necrosis factor-α (TNF-α) is involved in the differentiation of DPSCs under pro-inflammatory stimuli, but the mechanism of action of TNF-α is unknown. Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK) is a biomarker of an early inflammatory response that plays a key role in modulating cell differentiation, but the role of RICK in DPSCs is still unclear. In this study, we identified that RICK regulates TNF-α-mediated odontogenic differentiation of DPSCs via the ERK signaling pathway. The expression of the biomarkers of odontogenic differentiation dental matrix protein-1 (DMP-1), dentin sialophosphoprotein (DSPP), biomarkers of odontogenic differentiation, increased in low concentration (1-10 ng/ml) of TNF-α and decreased in high concentration (50-100 ng/ml). Odontogenic differentiation increased over time in the odontogenic differentiation medium. In the presence of 10 ng/L TNF-α, the expression of RICK increased gradually over time, along with odontogenic differentiation. Genetic silencing of RICK expression reduced the expression of odontogenic markers DMP-1 and DSPP. The ERK, but not the NF-κB signaling pathway, was activated during the odontogenic differentiation of DPSCs. ERK signaling modulators decreased when RICK expression was inhibited. PD98059, an ERK inhibitor, blocked the odontogenic differentiation of DPSCs induced by TNF-α. These results provide a further theoretical and experimental basis for the potential use of RICK in targeted therapy for dentin regeneration.
牙髓干细胞（DPSCs）具有自我更新和多向分化能力，在牙本质形成过程中发挥着积极作用。研究表明，肿瘤坏死因子-α（TNF-α）在促炎刺激下参与DPSCs的分化，但TNF-α的作用机制尚不清楚。Rip样相互作用半胱天冬酶样凋亡调节蛋白激酶（RICK）是早期炎症反应的生物标志物，在调节细胞分化中起关键作用，但RICK在DPSCs中的作用仍不明确。在本研究中，我们发现RICK通过ERK信号通路调节TNF-α介导的DPSCs成牙分化。低浓度（1-10 ng/ml）TNF-α可使成牙分化生物标志物牙本质基质蛋白-1（DMP-1）、牙本质涎磷蛋白（DSPP）的表达增加，高浓度（50-100 ng/ml）则使其表达降低。在成牙分化培养基中，成牙分化随时间增加。在10 ng/L TNF-α存在下，RICK的表达随时间逐渐增加，同时成牙分化也增加。RICK表达的基因沉默降低了成牙标志物DMP-1和DSPP的表达。在DPSCs成牙分化过程中，ERK信号通路而非NF-κB信号通路被激活。当RICK表达被抑制时，ERK信号调节剂减少。ERK抑制剂PD98059可阻断TNF-α诱导的DPSCs成牙分化。这些结果为RICK在牙本质再生靶向治疗中的潜在应用提供了进一步的理论和实验依据。
