Department of Life Sciences, Pohang University of Science and Technology , Pohang, Gyeongbuk 37673, Korea.
Biomedical Research Institute, Seoul National University Hospital , Seoul 110-744, Korea.
ACS Nano. 2015 Dec 22;9(12):11718-27. doi: 10.1021/acsnano.5b02997. Epub 2015 Nov 3.
The current diabetes mellitus pandemic constitutes an important global health problem. Reductions in the mass and function of β-cells contribute to most of the pathophysiology underlying diabetes. Thus, physiological control of blood glucose levels can be adequately restored by replacing functioning β-cell mass. Sources of functional islets for transplantation are limited, resulting in great interest in the development of alternate sources, and recent progress regarding cell fate change via utilization of extracellular vesicles, also known as exosomes and microvesicles, is notable. Thus, this study investigated the therapeutic capacity of extracellular vesicle-mimetic nanovesicles (NVs) derived from a murine pancreatic β-cell line. To differentiate insulin-producing cells effectively, a three-dimensional in vivo microenvironment was constructed in which extracellular vesicle-mimetic NVs were applied to subcutaneous Matrigel platforms containing bone marrow (BM) cells in diabetic immunocompromised mice. Long-term control of glucose levels was achieved over 60 days, and differentiation of donor BM cells into insulin-producing cells in the subcutaneous Matrigel platforms, which were composed of islet-like cell clusters with extensive capillary networks, was confirmed along with the expression of key pancreatic β-cell markers. The resectioning of the subcutaneous Matrigel platforms caused a rebound in blood glucose levels and confirmed the source of functioning β-cells. Thus, efficient differentiation of therapeutic insulin-producing cells was attained in vivo through the use of extracellular vesicle-mimetic NVs, which maintained physiological glucose levels.
当前的糖尿病流行是一个重要的全球健康问题。β细胞的质量和功能的减少导致了糖尿病的大部分病理生理学基础。因此，通过替换具有功能的β细胞质量，可以充分恢复血糖水平的生理控制。用于移植的功能性胰岛的来源有限，这导致人们对替代来源的开发产生了极大的兴趣，并且最近在利用细胞外囊泡（也称为外泌体和微泡）改变细胞命运方面取得了进展，值得注意。因此，本研究调查了来源于小鼠胰腺β细胞系的细胞外囊泡模拟纳米囊泡（NVs）的治疗能力。为了有效地分化产生胰岛素的细胞，构建了一个三维体内微环境，将细胞外囊泡模拟的 NVs 应用于包含骨髓（BM）细胞的糖尿病免疫缺陷小鼠的皮下 Matrigel 平台。在 60 天的时间内实现了血糖水平的长期控制，并且在由具有广泛毛细血管网络的胰岛样细胞簇组成的皮下 Matrigel 平台中，确认了供体 BM 细胞分化为产生胰岛素的细胞，同时表达了关键的胰腺β细胞标志物。对皮下 Matrigel 平台的切除导致血糖水平反弹，并证实了具有功能的β细胞的来源。因此，通过使用细胞外囊泡模拟 NVs 可以在体内有效地分化出治疗性胰岛素产生细胞，从而维持生理血糖水平。
