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群，其中含有产生胰岛素的细胞。将这些细胞移植到不能产生胰岛素的1型糖尿病患者的肝脏中，是对糖尿病控制不佳患者的一种既定的临床干预措施。然而，这种治疗方法无法治愈，大多数患者无法实现胰岛素独立，移植胰岛的胰岛素分泌随着时间的推移而减少。该项目将专注于通过在临床前模型中移植具有间充质基质细胞（MSCs）的特定细胞的胰岛来改善结果。间充质干细胞具有免疫调节、抗炎和促进再生的特性。该项目的主要目标是从储存的组织中开发一种“现成的”同种异体间充质干细胞，无需进一步匹配供体和受体。SNBTS的细胞专家已经从人体组织中制造出符合GMP标准的间质干细胞。我们已经证明，这些间充质干细胞与胰岛的联合移植改善了糖尿病小鼠模型中的胰岛移植结果，与仅接受胰岛的小鼠相比，8只接受联合输注的小鼠中有6只糖尿病治愈。Mountford J et al., Science Translational Medicine, 2021)。在这个项目中，重点将是进一步开发这些细胞用于临床。重点将放在：这些细胞在我们的糖尿病啮齿动物体内模型中的传递方法，考虑细胞的最佳剂量和状态（激活与非激活），并检查其解冻后的功效。

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.