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(T1D)的前景，而不仅仅是用胰岛素治疗症状。然而，胰岛移植作为一种治疗方法的主要问题是移植后24-48小时内发生的移植物功能显著丧失(高达80%)。这种功能丧失的部分原因是移植物中孤立的胰岛很脆弱，很容易受损，部分原因是移植物的环境，在肝脏血流中，通过引起炎症来对移植物做出反应，从而不可逆转地损害胰岛。在实验动物中，将被称为间充质基质细胞(MSCs)的辅助细胞与胰岛共同移植可以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MSCs如何提高胰岛移植物的存活率和功能，以在“无MSC”系统中复制MSCs的有益效果。我们之前已经证明，MSCs的一些有益作用可以归因于它们分泌的生物活性分子，并且只需在移植前将分子提供给胰岛就可以复制。在这个项目中，我们计划观察MSCs可能影响胰岛功能的另外两种机制。首先，像许多其他类型的细胞一样，间充质干细胞通过运输生物活性分子和其他细胞成分来释放小的、膜结合的小泡(“细胞外小泡”；EVS)来与其他细胞交流。我们将评估使用MSC来源的EVS治疗胰岛是否对其功能存活和胰岛移植的结果产生有利影响。其次，我们最近报道，MSCs可以将其部分线粒体--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。我们将研究线粒体是如何在MSCs和胰岛细胞之间转移的，以及这是否与改善胰岛功能有关。从这个项目中获得的信息将告诉我们如何在移植前最好地设计人类胰岛的“无细胞”治疗，以提高胰岛移植物的功能存活率，特别是在移植后的头几天，从而改善单个移植物接受者的临床结果。

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.