Chen Xin, An Hong, Du Yongbiao, Zhong Hao, Zhang Fangfang, Zeng Xiaomei, Lv Fen, Tian Zhihua, Jiang Zaixue, Peng Qi, Li Zengbao, Li Siping, Zhong Baimao, Lu Xiaomei, Zhu Yinghua
Department of Genetic Medicine, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan, China.
Department of Medical and Molecular Genetics, Dongguan Institute of Pediatrics, Dongguan, China.
Stem Cell Res Ther. 2025 Jul 18;16(1):384. doi: 10.1186/s13287-025-04521-0.
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by absolute insulin (INS) deficiency. As key components of the immune system, macrophages play critical roles in T1DM-associated pancreatic β-cell damage and multiorgan inflammatory injuries. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-EXOs) have emerged as promising therapeutic agents for immune-related disorders due to their immunomodulatory properties and favorable safety profile. However, systematic investigations into the therapeutic potential of hucMSC-EXOs in T1DM are lacking. This study aimed to evaluate the systemic anti-inflammatory effects of hucMSC-EXOs in T1DM and identify their key bioactive components.
T1DM was induced in C57BL/6 male mice via streptozotocin, followed by intraperitoneal administration of hucMSC-EXOs. Systemic glucose metabolism, multiorgan pathology, and macrophage infiltration were assessed. In vitro, THP-1-derived macrophages were polarized to an M1 phenotype and treated with hucMSC-EXOs. Proteomic profiling, pharmacological inhibition, and functional assays were employed to identify critical exosomal components.
hucMSC-EXOs significantly reduced hyperglycemia, restored glucose tolerance, and attenuated structural damage in the pancreas, spleen, liver, kidney, and heart of T1DM mice (p < 0.05). Mechanistically, hucMSC-EXOs suppressed macrophage infiltration and proinflammatory cytokine secretion (IL-6, TNF-α, CCL-2) across tissues. Proteomic analysis revealed INS and superoxide dismutase 1 (SOD1) as enriched anti-inflammatory proteins in hucMSC-EXOs. Heat inactivation abolished their bioactivity, while pharmacological inhibition of INS (S961) or SOD1 (ATN-224) reversed hucMSC-EXOs-mediated suppression of macrophage activation (p < 0.01).
This study demonstrates that hucMSC-EXOs ameliorate T1DM- associated hyperglycemia and multiorgan inflammation by targeting macrophage polarization through delivery of INS and SOD1. Our study reveals that hucMSC-EXOs exert their anti-inflammatory effects through coordinated delivery of insulin and SOD1, establishing a protein-centric mechanism for exosome-mediated immunomodulation in T1DM.
1型糖尿病（T1DM）是一种以绝对胰岛素（INS）缺乏为特征的慢性自身免疫性疾病。巨噬细胞作为免疫系统的关键组成部分，在T1DM相关的胰腺β细胞损伤和多器官炎症损伤中起关键作用。人脐带间充质干细胞来源的外泌体（hucMSC-EXOs）因其免疫调节特性和良好的安全性，已成为免疫相关疾病有前景的治疗药物。然而，目前缺乏对hucMSC-EXOs在T1DM治疗潜力的系统研究。本研究旨在评估hucMSC-EXOs在T1DM中的全身抗炎作用，并确定其关键生物活性成分。
通过链脲佐菌素诱导C57BL/6雄性小鼠患T1DM，随后腹腔注射hucMSC-EXOs。评估全身葡萄糖代谢、多器官病理和巨噬细胞浸润情况。在体外，将THP-1来源的巨噬细胞极化为M1表型并用hucMSC-EXOs处理。采用蛋白质组学分析、药理学抑制和功能测定来鉴定关键的外泌体成分。
hucMSC-EXOs显著降低了T1DM小鼠的高血糖水平，恢复了葡萄糖耐量，并减轻了胰腺、脾脏、肝脏、肾脏和心脏的结构损伤（p < 0.05）。机制上，hucMSC-EXOs抑制了各组织中的巨噬细胞浸润和促炎细胞因子分泌（IL-6、TNF-α、CCL-2）。蛋白质组学分析显示INS和超氧化物歧化酶1（SOD1）是hucMSC-EXOs中富集的抗炎蛋白。热灭活消除了它们的生物活性，而对INS（S961）或SOD1（ATN-224）的药理学抑制逆转了hucMSC-EXOs介导的巨噬细胞激活抑制（p < 0.01）。
本研究表明，hucMSC-EXOs通过递送INS和SOD1靶向巨噬细胞极化，改善T1DM相关的高血糖和多器官炎症。我们的研究表明，hucMSC-EXOs通过协同递送胰岛素和SOD1发挥其抗炎作用，建立了一种以蛋白质为中心的机制，用于T1DM中外泌体介导的免疫调节。
