Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China.
Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, People's Republic of China.
Int J Nanomedicine. 2024 Sep 14;19:9575-9596. doi: 10.2147/IJN.S459077. eCollection 2024.
The depletion of β cell mass is widely recognized as a significant contributor to the progression of type 2 diabetes mellitus (T2DM). Exosomes derived from mesenchymal stem cells (MSC-EXOs) hold promise as cell-free therapies for treating T2DM. However, the precise effects and mechanisms through which MSC-EXO affects β cell function remain incompletely understood, and the limited ability of MSC-EXO to target β cells and the short blood circulation time hampers its therapeutic effectiveness.
The effects of MSC-EXO were investigated in T2DM mice induced by a high-fat diet combined with STZ. Additionally, the high glucose-stimulated INS-1 cell line was used to investigate the potential mechanism of MSC-EXO. Michael addition reaction-mediated chemical coupling was used to modify the surface of the exosome membrane with a β-cell-targeting aptamer and polyethylene glycol (PEG). The β-cell targeting and blood circulation time were evaluated, and whether this modification enhanced the islet-protective effect of MSC-EXO was further analyzed.
We observed that the therapeutic effects of MSC-EXO on T2DM manifested through the reduction of random blood glucose levels, enhancement of glucose and insulin tolerance, and increased insulin secretion. These effects were achieved by augmenting β cell mass via inhibiting nuclear factor erythroid 2-related factor 2 (NRF2)-mediated ferroptosis. Mechanistically, MSC-EXOs play a role in the NRF2-mediated anti-ferroptosis mechanism by transporting active proteins that are abundant in the AKT and ERK pathways. Moreover, compared to MSC-EXOs, aptamer- and PEG-modified exosomes (Apt-EXOs) were more effective in islet protection through PEG-mediated cycle prolongation and aptamer-mediated β-cell targeting.
MSC-EXO suppresses NRF2-mediated ferroptosis by delivering bioactive proteins to regulate the AKT/ERK signaling pathway, thereby improving the function and quantity of β cells. Additionally, Apt-EXO may serve as a novel drug carrier for islet-targeted therapy.
β 细胞数量的减少被广泛认为是 2 型糖尿病（T2DM）进展的一个重要因素。间充质干细胞（MSC）衍生的外泌体有望成为治疗 T2DM 的无细胞治疗方法。然而，MSC-EXO 影响β 细胞功能的确切作用和机制仍不完全清楚，并且 MSC-EXO 靶向β 细胞的能力有限和血液循环时间短限制了其治疗效果。
在高脂肪饮食联合 STZ 诱导的 T2DM 小鼠中研究了 MSC-EXO 的作用。此外，还使用高葡萄糖刺激的 INS-1 细胞系研究了 MSC-EXO 的潜在机制。迈克尔加成反应介导的化学偶联用于用β 细胞靶向适体和聚乙二醇（PEG）修饰外泌体膜。评估了β 细胞靶向和血液循环时间，并且进一步分析了这种修饰是否增强了 MSC-EXO 的胰岛保护作用。
我们观察到 MSC-EXO 对 T2DM 的治疗效果表现为降低随机血糖水平、增强葡萄糖和胰岛素耐量以及增加胰岛素分泌。这些作用是通过抑制核因子红细胞 2 相关因子 2（NRF2）介导的铁死亡来增加β 细胞质量来实现的。从机制上讲，MSC-EXO 通过运输 AKT 和 ERK 途径中丰富的活性蛋白在 NRF2 介导的抗铁死亡机制中发挥作用。此外，与 MSC-EXO 相比，适体和 PEG 修饰的外泌体（Apt-EXO）通过 PEG 介导的循环延长和适体介导的β 细胞靶向在胰岛保护方面更有效。
MSC-EXO 通过递送生物活性蛋白来抑制 NRF2 介导的铁死亡，从而调节 AKT/ERK 信号通路，从而改善β 细胞的功能和数量。此外，Apt-EXO 可能成为胰岛靶向治疗的新型药物载体。
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