Generating novel sources of stem cells for regenerative and anti-infective applications

细菌对抗生素的耐药性被公认为对动物和人类健康的主要威胁，迫切需要寻找抗生素普遍使用的替代品。该项目的目的是开发强有力的方法，将间充质干细胞/基质细胞(MSC)制剂及其产品(例如外切体)作为无细胞现成产品，用于组织再生应用，包括作为抗感染药物和抗菌素耐药性(AMR)。最近的工作[1，2]，包括我们实验室的工作[3]，表明MSCs和他们的条件培养液(CM/exosome)不仅可以用于治疗动物的感染，也可以用于治疗狗的多药耐药细菌和临床牛乳房炎，也可以用于人类治疗移植物抗宿主病、急性呼吸窘迫综合征和新冠肺炎，以及多药耐药结核病。该项目将致力于从相关的大型动物模型中制备无细胞外体制剂，以阐明支持MSCs再生和抗微生物特性的机制，并着眼于开发新型的治疗性无细胞产品。这项研究还可能导致新的MSC衍生因子的鉴定，与目前商业上可用的MSC疗法相比，这些因子作为无细胞治疗产品具有优势。冷志等人。(2020)。血管紧张素转换酶2(-)骨髓间充质干细胞移植改善新冠肺炎肺炎患者的预后。老龄化指数11：216-228.2。Johnson V等人的研究成果。(2017年)。激活的间充质干细胞与抗生素和宿主先天免疫反应相互作用以控制慢性细菌感染。SCI Rep 7：9575.3。Cortes-Araya Y等人。(2018)。马骨髓、子宫内膜和脂肪组织间充质干细胞的抗菌活性和免疫学特性比较干细胞开发27：1518-1525。

Bacterial resistance to antibiotics is well recognised as a major threat to animal and human health and there is an urgent need to find alternatives to the generalized use of antibiotics. The aim of this project is to develop robust approaches for the application of mesenchymal stem/stromal cell (MSC) preparations, and their products (e.g. exosomes) as cell-free off-the-shelf products, for tissue regeneration applications, including as anti-infectives and to combat antimicrobial resistance (AMR). Recent work [1,2], including from our laboratory [3], showed that MSCs and their conditioned media (CM/exosomes) can be used in the treatment of infection not only in animals, in multiple-drug resistant bacteria (MDR) in dogs and clinical bovine mastitis, but also in humans to treat GvHD, ARDS and Covid-19, and MDR tuberculosis. This project will aim to produce exosome cell-free-preparations from relevant large animal models towards the elucidation of the mechanisms underpinning MSCs regeneration and anti-microbial properties, and with a view to develop novel therapeutic cell-free products. This investigation may also lead to the identification of novel MSC-derived factors which could provide advantages as cell-free therapeutic products compared to current available commercially MSC therapies.References1. Leng Z, et al. (2020). Transplantation of ACE2(-) Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging Dis 11:216-228.2. Johnson V, et al. (2017). Activated Mesenchymal Stem Cells Interact with Antibiotics and Host Innate Immune Responses to Control Chronic Bacterial Infections. Sci Rep 7:9575.3. Cortes-Araya Y, et al. (2018). Comparison of Antibacterial and Immunological Properties of Mesenchymal Stem/Stromal Cells from Equine Bone Marrow, Endometrium, and Adipose Tissue. Stem Cells Dev 27:1518-1525.