Cao Yangyang, Wang Yantong, Xia Dengsheng, Fan Zhipeng
Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.
Department of General Dentistry and Integrated Emergency Dental Care, Capital Medical University School of Stomatology, Beijing, China.
Cell Prolif. 2025 Feb;58(2):e13756. doi: 10.1111/cpr.13756. Epub 2024 Oct 2.
How to improve the neurogenic potential of mesenchymal stem cells (MSCs) and develop biological agent based on the underlying epigenetic mechanism remains a challenge. Here, we investigated the effect of histone demethylase Lysine (K)-specific demethylase 2B (KDM2B) on neurogenic differentiation and nerve injury repair by using MSCs from dental apical papilla (SCAP). We found that KDM2B promoted the neurogenic indicators expression and neural spheres formation in SCAP, and modified the Histone H3K4 trimethylation (H3K4me3) methylation on neurogenesis-related genes. KDM2B improved the SCAP mediated recovery of motor ability at the early healing stage of spinal cord injury rats. Meanwhile, KDM2B acted as a negative regulator to its partner EZH2 during neurogenic differentiation, enhancer of zeste homologue 2 (EZH2) suppressed the neurogenic ability of SCAP. Further, the protein interaction between KDM2B and EZH2 was identified which decreased during neurogenic differentiation. On this basis, we revealed seven key protein binding sequences of KDM2B to EZH2, and synthesized KDM2B-peptides based on these sequences. By the usage of KDM2B-peptides, EZH2 function was effectively intervened and the neurogenic ability of SCAP was promoted. More, KDM2B-peptides significantly improved the SCAP mediated functional recovery at SCI early phase. Our study revealed that KDM2B acted as a promotor to neurogenic differentiation ability of dental MSCs through binding and negatively regulating EZH2, and provided the KDM2B-peptides as candidate agents for improving the neurogenic ability of MSCs and nerve injury repair.
如何提高间充质干细胞（MSCs）的神经源性潜能，并基于潜在的表观遗传机制开发生物制剂仍然是一个挑战。在此，我们利用根尖乳头干细胞（SCAP）研究了组蛋白去甲基化酶赖氨酸（K）特异性去甲基化酶2B（KDM2B）对神经源性分化和神经损伤修复的影响。我们发现KDM2B促进了SCAP中神经源性指标的表达和神经球的形成，并改变了神经发生相关基因上的组蛋白H3K4三甲基化（H3K4me3）甲基化。KDM2B改善了脊髓损伤大鼠早期愈合阶段SCAP介导的运动能力恢复。同时，在神经源性分化过程中，KDM2B作为其伙伴EZH2（zeste同源物2增强子，EZH2）的负调节因子，EZH2抑制了SCAP的神经源性能力。此外，还鉴定了KDM2B与EZH2之间的蛋白质相互作用，该相互作用在神经源性分化过程中减少。在此基础上，我们揭示了KDM2B与EZH2的七个关键蛋白结合序列，并基于这些序列合成了KDM2B肽。通过使用KDM2B肽，EZH2的功能得到有效干预，SCAP的神经源性能力得到促进。此外，KDM2B肽显著改善了SCI早期SCAP介导的功能恢复。我们的研究表明，KDM2B通过结合并负调节EZH2，作为牙源性间充质干细胞神经源性分化能力的促进因子，并提供KDM2B肽作为提高间充质干细胞神经源性能力和神经损伤修复的候选药物。
