College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Cell Transplant. 2012;21(8):1775-89. doi: 10.3727/096368912X640628. Epub 2012 May 14.
Pancreatic islet transplantation is a promising method for curing diabetes mellitus. We proposed in this study a molecularly engineered islet cell clusters (ICCs) that could overcome problems posed by islet transplantation circumstances and host's immune reactions. A gene containing highly releasable exendin-4, an insulinotropic protein, was delivered into single islet cells to enhance glucose sensitivity; thereafter, the cells were reaggregated into small size ICCs. Then the surface of ICCs was modified with biocompatible poly(ethylene glycol)-lipid (PEG) (C18) for preventing immune reactions. The regimen of ICCs with low doses of anti-CD154 mAb and tacrolimus could effectively maintain the normal glucose level in diabetic mice. This molecularly engineered PEG-Sp-Ex-4 ICC regimen prevented cell death in transplantation site, partly through improving the regulation of glucose metabolism and by preventing hypoxia- and immune response-induced apoptosis. Application of this remedy is also potentially far-reaching; one would be to help overcome islet supply shortage due to the limited availability of pancreas donors and reduce the immunosuppressant regimens to eliminate their adverse effects.
胰岛细胞移植是治疗糖尿病的一种很有前途的方法。我们在这项研究中提出了一种分子工程化的胰岛细胞簇（ICCs），可以克服胰岛移植环境和宿主免疫反应带来的问题。将含有高可释放外泌素-4（一种胰岛素促分泌蛋白）的基因递送到单个胰岛细胞中，以增强葡萄糖敏感性；然后，将这些细胞重新聚集为小尺寸的 ICCs。然后，用生物相容性聚乙二醇-脂质（PEG）（C18）修饰 ICCs 的表面，以防止免疫反应。用低剂量抗 CD154 mAb 和他克莫司治疗 ICCs 的方案可以有效地维持糖尿病小鼠的正常血糖水平。这种分子工程化的 PEG-Sp-Ex-4 ICC 方案可防止移植部位的细胞死亡，部分原因是通过改善葡萄糖代谢的调节和防止缺氧和免疫反应诱导的细胞凋亡。这种治疗方法的应用也具有潜在的深远意义；一种方法是帮助克服由于胰腺供体有限而导致的胰岛供应短缺，并减少免疫抑制剂方案以消除其不良影响。
