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Background <p>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.</p> Methods <p>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 <i>vitro</i>, 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.</p> Results <p>hucMSC-EXOs significantly reduced hyperglycemia, restored glucose tolerance, and attenuated structural damage in the pancreas, spleen, liver, kidney, and heart of T1DM mice (<i>p</i> &lt; 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 (<i>p</i> &lt; 0.01).</p> Conclusions <p>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.</p>

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hucMSC-derived exosomes targeting macrophage polarization attenuate systemic inflammation in T1DM via INS/SOD1 delivery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月18日

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  • Xin Chen,
  • Hong An,
  • Yongbiao Du,
  • Hao Zhong,
  • Fangfang Zhang,
  • Xiaomei Zeng,
  • Fen Lv,
  • Zhihua Tian,
  • Zaixue Jiang,
  • Qi Peng,
  • Zengbao Li,
  • Siping Li,
  • Baimao Zhong,
  • Xiaomei Lu,
  • Yinghua Zhu

摘要

Background

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.

Methods

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.

Results

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).

Conclusions

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.