Liu Anqi, Peng Peng, Wei Changze, Meng Fanhui, Huang Xiaoyao, Liu Peisheng, Fan Siyuan, Cai Xinyue, Wu Meiling, Xuan Zilin, Liu Qing, Qiu Xinyu, Zhu Zhenlai, Guo Hao
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Disease, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Department of Stomatology, 985 Hospital of Joint Logistics Support Force, Taiyuan, Shanxi, 030000, China.
Adv Sci (Weinh). 2025 Jun;12(22):e2407446. doi: 10.1002/advs.202407446. Epub 2025 Mar 16.
Apoptosis is crucial for maintaining internal homeostasis. Apoptotic vesicles (ApoVs) derived from mesenchymal stem/ stromal cells (MSCs-ApoVs) as natural lipid nanoparticles are attractive candidates for the next generation of immunotherapies. However, the therapeutic potential of MSCs-ApoVs in managing hypersensitivity reactions mediated by CD8 T cells remains elusive. This research utilized contact hypersensitivity and oral lichenoid reaction models, both of which represent type IV hypersensitivity reactions. ApoVs are shown that derived from stem cells from human exfoliated deciduous teeth (SHED-ApoVs), a subtype of MSCs, directly fused with the plasma membrane of CD8 T cells, subsequently increasing membrane permeability through L-type voltage-gated Ca channels. This initiates a cascade of events including calcium overload, mitochondrial dysfunction, and the initiation of apoptosis in these cells. As known, this is the first study to characterize SHED-ApoVs as immune microenvironment modulators, demonstrating their therapeutic potential and mechanism in these reactions. Moreover, analysis of blood samples from patients with oral lichenoid reactions verified the antihypersensitivity property of SHED-ApoVs. This study sheds light on the therapeutic prospects of MSCs-ApoVs and their underlying mechanisms in diseases mediated by CD8 T cells, contributing novel perspectives for the clinical application of ApoVs and nanovesicle-based cell-free therapies.
细胞凋亡对于维持体内稳态至关重要。源自间充质干/基质细胞的凋亡小泡（MSCs-ApoVs）作为天然脂质纳米颗粒，是下一代免疫疗法的有吸引力的候选者。然而，MSCs-ApoVs在管理由CD8 T细胞介导的超敏反应中的治疗潜力仍然难以捉摸。本研究利用接触性超敏反应和口腔苔藓样反应模型，这两种模型均代表IV型超敏反应。研究表明，源自人脱落乳牙干细胞的凋亡小泡（SHED-ApoVs），即MSCs的一种亚型，直接与CD8 T细胞的质膜融合，随后通过L型电压门控钙通道增加膜通透性。这引发了一系列事件，包括钙超载、线粒体功能障碍以及这些细胞中凋亡的启动。众所周知，这是第一项将SHED-ApoVs表征为免疫微环境调节剂的研究，证明了它们在这些反应中的治疗潜力和机制。此外，对口腔苔藓样反应患者血液样本的分析证实了SHED-ApoVs的抗过敏特性。本研究揭示了MSCs-ApoVs在由CD8 T细胞介导的疾病中的治疗前景及其潜在机制，为ApoVs和基于纳米小泡的无细胞疗法的临床应用提供了新的视角。
