Improving beta cell function by mesenchymal stromal cells: novel mechanisms and cell-free translational potential

胰岛移植提供了治愈1型糖尿病（T1 D）的前景，而不仅仅是用胰岛素治疗症状。然而，胰岛移植作为治疗的主要问题是移植物功能的显著丧失（高达80%），其发生在移植后立即的24-48小时内。这种功能丧失部分是因为移植物中的孤立胰岛是脆弱的，容易受损，部分是因为肝血流内的移植物环境通过引起炎症对移植物产生反应，这不可逆地损害胰岛。在实验动物中，将称为间充质基质细胞（MSC）的“辅助”细胞与胰岛共同移植可改善移植物功能和存活率，并抑制炎症，但这在临床人类胰岛移植中在技术上是不可行的。因此，我们正在研究MSC如何提高胰岛移植物的存活率和功能，以复制MSC在“无MSC”系统中的有益作用。我们以前已经表明，MSC的一些有益作用可以归因于它们分泌的生物活性分子，并且可以仅通过在移植前向胰岛提供分子来复制。在这个项目中，我们计划研究MSC可能影响胰岛功能的另外两种机制。首先，与许多其他细胞类型一样，MSC释放小的膜结合囊泡（“细胞外囊泡”; EV）以通过运输生物活性分子和其他细胞组分与其他细胞通信。我们将评估用MSC衍生的EV治疗胰岛是否对它们的功能存活率以及胰岛移植的结果有有益的影响。其次，我们最近报道了MSC可以将它们的一些线粒体-对正常细胞功能至关重要的亚细胞器-转移到功能受损的胰岛细胞。我们将研究线粒体如何在MSC和胰岛细胞之间转移，以及这是否与改善胰岛功能有关。从该项目中获得的信息将告知如何在移植前最好地设计人类胰岛的“无细胞”治疗，以改善胰岛移植物的功能存活，特别是在移植后的最初几天内，从而改善个体移植受体的临床结果。

Islet transplantation offers the prospect of a cure for type 1 diabetes (T1D) rather than merely treating the symptoms with insulin. However, a major problem with islet transplantation as a treatment is the significant loss of graft function (up to 80%) which occurs in the 24-48 hours immediately after transplantation. This loss of function is partly because the isolated islets in the graft are fragile and easily damaged, and partly because the graft environment, inside the liver bloodstream, reacts to the graft by causing inflammation which irreversibly damages the islets. In experimental animals co-transplanting "helper" cells known as mesenchymal stromal cells (MSCs) with islets improves graft function and survival, and suppresses inflammation, but this is not technically feasible in clinical human islet transplants. We are therefore studying how MSCs improve islet graft survival and function to replicate the beneficial effects of MSCs in an "MSC-free" system. We have previously shown that some of the beneficial effects of MSCs can be attributed to biologically active molecules which they secrete and can be replicated merely by supplying the molecules to the islets before transplantation. In this project we plan to look at two other mechanisms through which MSCs may influence islet function. First, like many other cell types, MSC release small, membrane bound vesicles ("extracellular vesicles"; EVs) to communicate with other cells by transporting biologically active molecules and other cellular components. We will assess whether treating islets with MSC-derived EVs has beneficial effects on their functional survival and thus on the outcomes of islet transplantation. Second, we have recently reported that MSCs can transfer some of their mitochondria - subcellular organelles which are vital for normal cell function - to functionally-compromised islet cells. We will investigate how mitochondria are transferred between MSCs and islet cells, and whether this is associated with improved islet function. Information gained from this project will inform how best to design "cell-free" treatments of human islets prior to transplantation to improve the functional survival of the islet graft, particularly within the first few days after transplantation, and so improve the clinical outcomes for individual graft recipients.