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<p>Aggregated mesenchymal stromal cells (MSCs) show enhanced anaerobic glycolysis and elevated lactate production when compared to conventional adherent MSCs. It is unknown whether their extracellular vesicles (EVs) inherit lactate from parent cells and regulate anaerobic glycolysis in recipient cells. Here we show that aggregated MSC-derived EVs (agg-EVs) have superior therapeutic effects on type 1 diabetes mellitus (T1DM) with significantly reduced hyperglycemia, improved pancreatic islets, and elevated CD8<sup>+</sup> T cell exhaustion. Mechanistically, we found that agg-EVs inherited lactate from aggregated MSCs to enhance L-cysteine decomposition in CD8<sup>+</sup> T cells. Non-targeted metabolomics analysis revealed that agg-EV-treated CD8<sup>+</sup> T cells showed elevated L-cysteine metabolism as well as reduced L-cysteine, glutathione (GSH) and GSH/GSSG (glutathione disulfide) ratio, resulting in an increased hydrogen sulfide (H<sub>2</sub>S) level. H<sub>2</sub>S can activate β-catenin to upregulate programmed cell death protein 1 (PD-1) expression and, therefore, suppress CD8<sup>+</sup> T cell proliferation and function. Blockage of L-cysteine decomposition by knockdown pyruvate kinase M2 (PKM2) in aggregated MSCs or knockout of cystathionine γ-lyase to reduce H<sub>2</sub>S level in CD8<sup>+</sup> cells diminished agg-EV-mediated therapeutic effects. These findings identify a previously unknown mechanism by which agg-EVs induce CD8<sup>+</sup> T cell exhaustion <i>via</i> H<sub>2</sub>S/β-catenin/PD-1 axis in T1DM immunotherapy.</p> Graphical Abstract <p></p>

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Extracellular vesicles inherit lactate from aggregated MSCs to alleviate type 1 diabetes mellitus via H2S-induced CD8+ T cell exhaustion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Qianhui Ren,
  • Qianmin Ou,
  • Zhengshi Li,
  • Luhan Niu,
  • Deqian Tang,
  • Xinyu Liu,
  • Xueli Mao,
  • Songtao Shi

摘要

Aggregated mesenchymal stromal cells (MSCs) show enhanced anaerobic glycolysis and elevated lactate production when compared to conventional adherent MSCs. It is unknown whether their extracellular vesicles (EVs) inherit lactate from parent cells and regulate anaerobic glycolysis in recipient cells. Here we show that aggregated MSC-derived EVs (agg-EVs) have superior therapeutic effects on type 1 diabetes mellitus (T1DM) with significantly reduced hyperglycemia, improved pancreatic islets, and elevated CD8+ T cell exhaustion. Mechanistically, we found that agg-EVs inherited lactate from aggregated MSCs to enhance L-cysteine decomposition in CD8+ T cells. Non-targeted metabolomics analysis revealed that agg-EV-treated CD8+ T cells showed elevated L-cysteine metabolism as well as reduced L-cysteine, glutathione (GSH) and GSH/GSSG (glutathione disulfide) ratio, resulting in an increased hydrogen sulfide (H2S) level. H2S can activate β-catenin to upregulate programmed cell death protein 1 (PD-1) expression and, therefore, suppress CD8+ T cell proliferation and function. Blockage of L-cysteine decomposition by knockdown pyruvate kinase M2 (PKM2) in aggregated MSCs or knockout of cystathionine γ-lyase to reduce H2S level in CD8+ cells diminished agg-EV-mediated therapeutic effects. These findings identify a previously unknown mechanism by which agg-EVs induce CD8+ T cell exhaustion via H2S/β-catenin/PD-1 axis in T1DM immunotherapy.

Graphical Abstract