Recapitulating beta cell development adjacent to the islet vascular niche to advance beta cell replacement therapies for type 1 diabetes.

1型糖尿病（T1 D）是一种自身免疫性疾病，其中免疫细胞破坏位于胰岛中的β细胞。由于β细胞的主要作用是产生胰岛素和降低血糖，患有T1 D的人缺乏足够的胰岛素，导致高血糖水平，这使他们患血管，神经元，肾脏和其他疾病的风险增加。T1 D最常见的治疗是通过泵或每日注射给予胰岛素，这是一种负担，因为它不是治愈方法，并且可能会偶尔失败。来自器官捐献者的β细胞移植为T1 D提供了长期治疗，改善了大多数接受者的血糖控制和生活质量，并消除了某些患者对胰岛素给药的需求。然而，器官捐献者短缺;因此，科学界旨在开发用于移植的β细胞的替代来源。为了做到这一点，人类干细胞，这是有潜力产生所有人体器官的细胞，已被引导到胰腺细胞类型，如β细胞，目前正在临床试验中评估其安全性和功能。来自这些试验的报告指出了两个主要挑战：（i）移植后存活率差;（ii）响应于葡萄糖的胰岛素分泌不足。在这个建议中，我设计了可以解决这两个问题的实验。我以前的工作表明，将胰腺细胞连接到血管可以输送氧气，营养物质和信号分子，这些分子在移植到糖尿病小鼠后生存，感知葡萄糖和分泌胰岛素。因此，在这项提案中，我的目标是在这项研究的基础上产生血管化的β细胞，以增强其功能，同时提高其移植后的存活率。

Type 1 diabetes (T1D) is an autoimmune disease in which the immune cells destroy the beta cells located in the pancreatic islets of Langerhans. As the primary role of the beta cells is to produce insulin and lower blood sugar, people living with T1D lack sufficient insulin leading to high blood sugar levels, which puts them at increased risk of vascular, neuronal, kidney, and other diseases. The most common therapy for T1D is the administration of insulin through pumps or daily injections, which is burdensome as it is not a cure and could fail episodically. Transplantation of beta cells from organ donors offers long-term treatment for T1D, improves sugar control and quality of life in the majority of the recipients, and eliminates the need for insulin administration in certain patients. However, there is a shortage of organ donors; therefore, the scientific community aimed at developing alternative sources of beta cells for transplantation. To do so, human stem cells, which are cells with the potential to generate all human organs, have been guided towards pancreatic cell types such as the beta cells and are currently being assessed in clinical trials for safety and function. Reports from these trials indicated two major challenges: (i) poor survival after transplantation; (ii) insufficient insulin secretion in response to glucose. In this proposal, I have designed experiments that could address these two issues. My previous work demonstrated that connecting pancreatic cells to vessels allows the delivery of oxygen, nutrients, and signaling molecules required to survive, sense glucose and secrete insulin after transplantation into diabetic mice. Therefore, in this proposal, I aim to build on this study to generate vascularized beta cells to boost their function and simultaneously improve their survival post-transplantation.