Dental pulp stem cells (DPSCs) play a vital role in tooth restoration, regeneration, and homeostasis. The link between DPSC senescence and tooth aging has been well-recognized. ROR2 plays an important role in aging-related gene expression. However, the expression and function of ROR2 in DPSC aging remain largely unknown. In this study, we found that ROR2 expression was significantly decreased in aged pulp tissues and DPSCs. The depletion of ROR2 in young DPSCs inhibits their self-renewal capacity, while its overexpression in aged DPSCs restores their self-renewal capacity. Interestingly, we found that sphingomyelin (SM) is involved in the senescence of DPSCs regulated by ROR2. Mechanistically, we confirmed that ROR2 inhibited the phosphorylation of STK4, which promoted the translocation of Forkhead Box O1 (FOXO1) to the nucleus. STK4 inhibition or knockdown of FOXO1 markedly increased the proliferation of DPSCs and upregulated the expression of SMS1, which catalyzed SM biogenesis. Moreover, FOXO1 directly bound to the SMS1 promoter, repressing its transcription. Our findings demonstrated the critical role of the ROR2/STK4-FOXO1/SMS1 axis in the regulation of SM biogenesis and DPSC senescence, providing a novel target for antagonizing tooth aging.

中文翻译：

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ROR2下调通过抑制鞘磷脂生物合成中的STK4-FOXO1/SMS1轴促进牙髓干细胞衰老

牙髓干细胞 (DPSCs) 在牙齿修复、再生和体内平衡中发挥着至关重要的作用。DPSC 衰老与牙齿老化之间的联系已得到广泛认可。ROR2在衰老相关基因表达中起重要作用。然而，ROR2 在 DPSC 衰老中的表达和功能仍然很大程度上未知。在这项研究中，我们发现 ROR2 表达在老化的牙髓组织和 DPSCs 中显着降低。年轻 DPSCs 中 ROR2 的消耗抑制了它们的自我更新能力，而它在老年 DPSCs 中的过度表达恢复了它们的自我更新能力。有趣的是，我们发现鞘磷脂（SM）参与了由 ROR2 调节的 DPSCs 的衰老。机制上，我们证实 ROR2 抑制 STK4 的磷酸化，从而促进 Forkhead Box O1 (FOXO1) 易位至细胞核。STK4 抑制或 FOXO1 的敲低显着增加了 DPSCs 的增殖并上调了 SMS1 的表达，这催化了 SM 的生物发生。此外，FOXO1 直接与 SMS1 启动子结合，抑制其转录。我们的研究结果证明了 ROR2/STK4-FOXO1/SMS1 轴在调节 SM 生物发生和 DPSC 衰老中的关键作用，为对抗牙齿衰老提供了一个新的靶点。