Optimisation of Allogeneic GMP Grade Mesenchymal Stromal Cells To Promote The Long Term Engraftment And Function Of Islets

胰岛是胰腺内的细胞团，其中含有胰岛素产生细胞。将这些细胞移植到1型糖尿病患者的肝脏中，对于那些控制不佳的糖尿病患者来说，是一种既定的临床干预措施。根据定义，1型糖尿病患者无法产生胰岛素。然而，治疗无法治愈，大多数患者永远无法实现胰岛素独立，移植胰岛的胰岛素产生随着时间的推移而减少。该项目将致力于通过在临床前模型中将胰岛与称为间充质基质细胞(MSCs)的特定细胞一起移植来改善结果。MSCs具有免疫调节、抗炎和促再生等特性。该项目的主要目标是从储存的组织中开发出一种现成的同种异体间充质干细胞，不需要进一步的供者和接受者的匹配。SNBTS的细胞专家已经制造出了从人体组织到良好制造实践(GMP)级的MSCs。我们已经证明，与那些单独接受胰岛移植的小鼠相比，这些MSCs与胰岛联合移植改善了糖尿病小鼠模型中的胰岛移植结果，导致8只接受联合输注的小鼠中有6只糖尿病治愈(福布斯S...蒙特福德J等人，科学转化医学，2021年)。在这个项目中，重点将放在进一步开发这些细胞用于临床。重点将集中在：体内糖尿病啮齿动物模型中这些细胞的输送方法，考虑这些细胞的最佳剂量和状态(激活和非激活)，并检查它们在解冻后的效果。

Islets are clusters of cells within the pancreas which contain insulin producing cells. Transplantation of these cells into the liver of a patient with Type 1 diabetes, who by definition cannot produce insulin, is an established clinical intervention in those with poorly controlled diabetes. However, the treatment falls short of a cure and most patients never achieve insulin independence and insulin production of the transplanted islets decreases over time. This project will focus on improving outcomes by transplantation of islets with specific cells called mesenchymal stromal cells (MSCs) in pre-clinical models. MSCs have immunomodulatory, anti-inflammatory and pro-regenerative properties. The main aim of the project is to develop an "off-the-shelf", allogeneic MSCs from banked tissue requiring no further matching of donor to recipient.The cell experts in SNBTS have manufactured MSCs from human tissue to Good Manufacturing Practise (GMP) grade. We have shown that the co-transplantation of these MSCs with islets improves islet transplant outcomes in a diabetic mouse model leading to a cure of the diabetes in 6 out of 8 mice that received the co-infusion in contrast to those mice that received islets alone where no cure was demonstrated (Forbes S...Mountford J et al., Science Translational Medicine, 2021). In this project the focus will be on further developing these cells for clinical use. A focus will be on: the method of delivery of these cells in our in vivo diabetic rodent model, consideration of the optimum dose and state (activated vs. non-activated) of the cells and examining their efficacy post thawing.