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

iPSC-MSC来源的细胞外囊泡治疗干燥综合征或放疗引起的口干的机制

基本信息

批准号：
10701307
负责人：
Ryang Hwa Lee
金额：
$ 35.98万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2024-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10701307
关键词：
Adverse effects Affect Aging Anti-Inflammatory Agents Autoimmune Diseases Autoimmune Responses Biological Biological Products Bone Marrow Cell Therapy Cells Clinical Clinical Research Derivation procedure Disease Endothelial Cells Epithelial Cells Funding Goals Head and Neck Cancer Human Immune Immune response Impairment In Vitro Infusion procedures Laboratories Mediating Mesenchymal Mesenchymal Stem Cells Natural regeneration Organ Outcome Patients Production Property Proteomics Quality of life Radiation Radiation induced damage Radiation therapy Reproducibility Research Salivary Salivary Glands Sjogren&apos s Syndrome Spleen Standardization Stromal Cells Syndrome Testing Therapeutic Therapeutic Effect Tissues Treatment Efficacy United States National Institutes of Health Variant Work Xerostomia base clinical application clinical practice extracellular vesicles head and neck cancer patient immunoregulation improved induced pluripotent stem cell irradiation knock-down macrophage miRNA expression profiling mouse model nanoparticle novel overexpression paracrine preclinical study regenerative restoration saliva secretion side effect stem success tissue regeneration

项目摘要

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.

项目概要唾液分泌长期持续减少，也称为口干，在干燥病患者中很常见综合征（影响唾液腺的自身免疫性疾病）或接受头颈部放射治疗这种副作用会严重损害生活质量并且很难治愈。干/基质细胞（MSC）通常从组织中分离出来，能够抑制自身免疫反应和促进再生，并且对两种类型的口干均显示出治疗功效。然而，直接使用组织来源的 MSC 进行治疗存在许多局限性，包括其高申请人最近的工作表明，MSCs 来源于人类。诱导多能干细胞（iMSC）高度标准化，可以大规模生产。细胞外囊泡（EV）是细胞自发释放的纳米级颗粒，具有生物活性。分子与其来源细胞相似，相比之下更安全、更适合临床应用 iMSC 及其 EV 表现出免疫抑制和促再生作用。该提案旨在确定治疗潜力和 iMSC EV 对两种类型口干的机制首先，该项目将确定治疗机制。其次，该项目将确定治疗干燥综合征的方法。局部注入 iMSC EV 恢复局部放射后唾液分泌的机制。拟议的研究将为一种新颖且临床可行的方法提供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也会产生这些结果。鼓励对其他自身免疫性疾病或其他辐射损伤的类似疗法进行进一步研究健康的器官。