Type 1 diabetes (T1D) results from the autoimmune destruction of β-cells within the pancreatic islets of Langerhans. Clinical islet transplantation from healthy donors is proposed to ameliorate symptoms, improve quality of life, and enhance the life span of afflicted T1D patients. However, post-transplant outcomes are dependent on the survival of the transplanted islets, which relies on the engraftment of the islets with the recipient's vasculature among other factors. Treatment strategies to improve engraftment include combining islets with supporting cells including endothelial cells (EC) and mesenchymal stem cells (MSC), dynamic cells capable of robust immunomodulatory and vasculogenic effects. In this study, we developed an in vitro model of transplantation to investigate the cellular mechanisms that enhance rapid vascularization of heterotopic islet constructs. Self-assembled vascular beds of fluorescently stained EC served as reproducible in vitro transplantation sites. Heterotopic islet constructs composed of islets, EC, and MSC were transferred to vascular beds for modeling transplantation. Time-lapsed imaging was performed for analysis of the vascular bed remodeling for parameters of neo-vascularization. Moreover, sampling of media following modeled transplantation showed secretory profiles that were correlated with imaging analyses as well as with islet function using glucose-stimulated insulin secretion. Together, evidence revealed that heterotopic constructs consisting of islets, EC, and MSC exhibited the most rapid recruitment and robust branching of cells from the vascular beds suggesting enhanced neo-vascularization compared to islets alone and control constructs. Together, this evidence supports a promising cell transplantation strategy for T1D and also demonstrates a valuable tool for rapidly investigating candidate cellular therapies for transplantation.

中文翻译：

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使用体外平台评估1型糖尿病异位胰岛构建体的血管化。

1型糖尿病（T1D）是由Langerhans胰岛内β细胞的自身免疫破坏引起的。建议从健康捐献者那里进行临床胰岛移植，以改善症状，改善生活质量并延长患病的T1D患者的寿命。然而，移植后的结果取决于移植的胰岛的存活，这取决于其他因素中胰岛植入受体血管系统的情况。改善移植的治疗策略包括将胰岛与支持细胞（包括内皮细胞（EC）和间充质干细胞（MSC））结合在一起，这些细胞具有强大的免疫调节和血管生成作用。在这项研究中，我们开发了一种体外移植模型，以研究增强异位胰岛构建体快速血管生成的细胞机制。荧光染色EC的自组装血管床可作为体外移植部位的重现性。将由胰岛，EC和MSC组成的异位胰岛构建体转移到血管床中，以模拟移植。进行延时成像以分析血管床重塑的新血管形成参数。此外，在模型移植后对培养基进行采样显示分泌物谱与成像分析以及使用葡萄糖刺激的胰岛素分泌的胰岛功能相关。在一起的证据表明，异位构建体由胰岛，EC，MSC和MSC表现出最快速的从血管床募集和稳固的细胞分支，表明与单独的胰岛和对照构建体相比，新血管形成增强。总之，这一证据支持了有希望的T1D细胞移植策略，也证明了一种用于快速研究候选细胞疗法进行移植的有价值的工具。