Therapeutic mechanisms of iPSC-MSC derived extracellular vesicles on dry mouth caused by Sjorgren's syndrome or radiotherapy

项目摘要 唾液分泌的长期减少，也称为口干，在干燥的患者中很常见 综合征(一种影响唾液腺的自身免疫性疾病)或接受头颈部放射治疗 癌症。这种副作用严重损害了生活质量，而且很难补救。间充质 干细胞/基质细胞(MSCs)通常是从组织中分离出来的，能够抑制自身免疫 该药具有良好的疗效和促进再生的作用，对这两种类型的口干症都显示出治疗效果。 然而，直接使用组织来源的间充质干细胞进行治疗有许多局限性，包括它们的高 变化和有限的可扩展性。申请人最近的研究表明，骨髓间充质干细胞来源于人类 诱导多能干细胞(IMSCs)是高度标准化的，可以大规模生产。 细胞外小泡(EV)是细胞自发释放的纳米颗粒。电动汽车携带生物活性 与它们的原始细胞相似的分子相比，更安全，更适合临床应用 到它们的原始细胞。IMSCs及其EVS表现出免疫抑制和促进再生的作用 可与最好的组织来源的MSCs相媲美。这项提案旨在确定治疗潜力和 IMSC EVS对两种类型口干的作用机制。首先，这个项目将确定治疗机制 系统输注iMSC EVS治疗干燥综合征。其次，这个项目将决定治疗 局部输注iMSC EVS对局部照射后唾液分泌恢复的作用机制成功之路 将为新的临床可行的概念验证和优化指导 治疗干燥综合征和放射治疗引起的口干。这些结果也将 鼓励对其他自身免疫性疾病或其他疾病的辐射损伤进行类似疗法的进一步研究 健康的器官。

Project Summary The long lasting decrease of saliva secretion, also called dry mouth, is common in patients with Sjögren's syndrome (an autoimmune disease affecting salivary glands) or treated with radiation therapy for head and neck cancer. This side effect significantly impairs the quality of life and is difficult to remedy. Mesenchymal stem/stromal cells (MSCs) are conventionally isolated from tissues and capable of inhibiting autoimmune responses and promoting regeneration, and have shown therapeutic efficacies in both types of dry mouth. However, there are many limitations of using tissue-derived MSCs directly for therapies including their high variations and limited expandability. The applicant’s recent work revealed that MSCs derived from human induced pluripotent stem cells (iMSCs) are highly standardized and can be produced at a large scale. Extracellular vesicles (EVs) are nano-sized particles released from cells spontaneously. EVs carry bioactive molecules similar to their originating cells, and are much safer and more feasible for clinical application compared to their originating cells. iMSCs and their EVs showed immunosuppressive and pro-regenerative effects comparable to the best tissue-derived MSCs. This proposal aims to determine therapeutic potentials and mechanisms of iMSC EVs on both types of dry mouth. First, this project will determine therapeutic mechanisms of systemically infused iMSC EVs on Sjögren's syndrome. Second, this project will determine therapeutic mechanisms of locally infused iMSC EVs on the restoration of saliva secretion after local radiation. The success of proposed research will provide the proof-of-concept and optimization guide of a novel and clinically feasible therapy for both Sjögren's syndrome and dry mouth caused by radiation therapy. These outcomes will also encourage further research on similar therapies for other autoimmune diseases or radiation damages to other healthy organs.