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

项目摘要 唾液分泌的长期持续减少，也称为口干，在干燥症患者中很常见 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 癌这种副作用严重损害生活质量，难以补救。充质 干细胞/基质细胞（MSC）通常从组织中分离，并且能够抑制自身免疫 反应和促进再生，并已显示出对两种类型的口干的治疗效果。 然而，直接将组织来源的MSC用于治疗存在许多局限性，包括其高表达。 变化和有限的可扩展性。申请人最近的工作揭示了来源于人的MSC可以在体外被诱导。 诱导多能干细胞（iMSC）是高度标准化的，并且可以大规模生产。 细胞外囊泡是细胞自发释放的纳米级颗粒。EV携带生物活性 分子类似于它们的起源细胞，并且与它们的来源细胞相比， 到它们的原始细胞。iMSCs及其EV表现出免疫抑制和促再生作用 与最好的组织来源的MSC相当。该提案旨在确定治疗潜力， iMSC EV对两种类型口干的作用机制。首先，该项目将确定治疗机制 全身输注iMSC EV治疗干燥综合征的研究。第二，该项目将确定治疗 局部输注iMSC EV对局部辐射后唾液分泌恢复的机制。成功 提出的研究将提供一种新的和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。这些成果还将 鼓励进一步研究其他自身免疫性疾病或辐射损伤的类似疗法。 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.