Zheng Mengting, Chen Heng, Liu Zhonglong, Wang Zhouyang, Jiang Ting, He Yue
Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, People's Republic of China.
National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, 200011, People's Republic of China.
Stem Cell Res Ther. 2025 Jul 18;16(1):388. doi: 10.1186/s13287-025-04508-x.
Radiation-induced jaw injury is one of the most severe complications after radiotherapy for head and neck cancer, which can disrupt patients' health and quality of life. Although the direct target of inflammation and suppressed bone regeneration activity by ionizing radiation (IR) has been phenomenally observed, the underlying mechanisms and potential therapeutic targets remain blurred. Osteoimmunology emphasizes that dendritic cells (DCs) may contribute to bone diseases.
In this study, we assessed phenotypic and functional alterations of DCs in a radiation-induced jaw injury rat model through immunohistopathological staining. The effects of IR on bone marrow-derived dendritic cells (BMDCs) in vitro were further validated by flow cytometry, ELISA, mixed lymphocyte reaction (MLR) assay, and transwell. The cellular responses and differentiation of bone marrow mesenchymal stem cells (BMSCs) under BMDC-derived conditioned medium stimulation were evaluated through various cell staining, Quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. Flow cytometry, qRT-PCR, WB were employed to verify tolerogenic characteristics of Vitamin D3 (VitD3)-induced tolerogenic DCs (tolDCs). TolDCs were encapsulated in GelMA to develop an effective in vivo therapeutic approach for irradiated jaw defects.
We revealed that IR activated the mature-inflammatory phenotype and corresponding biological functions of DCs through the nuclear factor kappa-B (NF-κB) signaling pathway. Exposure to conditioned medium from irradiated BMDCs induced oxidative stress and inflammatory responses in BMSCs, inhibiting their proliferation, migration, and osteogenic potential while potentiating adipogenic capacity. Furthermore, tolDCs were proven to be resistant to radiation-induced activation. Local administration of tolDCs was effective in improving bone regeneration of irradiated jawbone defects.
Hyperactivation of DCs served as a potential pathogenic factor in radiation-induced jaw injury, exacerbating local inflammation and abrogating the biological functions of BMSCs. The local transplantation of tolDCs was a promising therapeutic strategy for osteogenesis in radiation-induced jaw injury.
放射性颌骨损伤是头颈部癌放疗后最严重的并发症之一，会破坏患者的健康和生活质量。尽管已经显著观察到电离辐射（IR）引起炎症和抑制骨再生活动的直接靶点，但潜在机制和潜在治疗靶点仍不明确。骨免疫学强调树突状细胞（DCs）可能与骨疾病有关。
在本研究中，我们通过免疫组织病理学染色评估了放射性颌骨损伤大鼠模型中DCs的表型和功能变化。通过流式细胞术、酶联免疫吸附测定（ELISA）、混合淋巴细胞反应（MLR）试验和transwell进一步验证了IR对体外骨髓来源树突状细胞（BMDCs）的影响。通过各种细胞染色、定量实时聚合酶链反应（qRT-PCR）和蛋白质印迹法评估了BMDC衍生条件培养基刺激下骨髓间充质干细胞（BMSCs）的细胞反应和分化。采用流式细胞术、qRT-PCR、蛋白质印迹法验证维生素D3（VitD3）诱导的耐受性DCs（tolDCs）的耐受性特征。将tolDCs包裹在甲基丙烯酰化明胶（GelMA）中，开发一种针对放射性颌骨缺损的有效体内治疗方法。
我们发现IR通过核因子κB（NF-κB）信号通路激活DCs的成熟炎症表型和相应的生物学功能。暴露于受辐射BMDCs的条件培养基会诱导BMSCs产生氧化应激和炎症反应，抑制其增殖、迁移和成骨潜能，同时增强其脂肪生成能力。此外，tolDCs被证明对辐射诱导的激活具有抗性。局部施用tolDCs可有效改善放射性颌骨缺损的骨再生。
DCs的过度激活是放射性颌骨损伤的潜在致病因素，加剧局部炎症并消除BMSCs的生物学功能。tolDCs的局部移植是放射性颌骨损伤骨生成的一种有前景的治疗策略。
