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

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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.