Mesenchymal stem cell - derived extracellular vesicles modulate immune function in sepsis

Severe sepsis is characterized by dysregulated immune responses associated with high mortality. Both hyperinflammation and progressive immunosuppression contribute to poor outcomes, yet reliable biomarkers and effective immunomodulatory therapies remain limited. Extracellular vesicles derived from induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-EVs) represent a promising cell-free therapeutic strategy, but their effects on immune dysfunction in human sepsis are poorly characterized.

Fifty-three patients with surgical sepsis meeting Sepsis-3 criteria were prospectively enrolled. Sixty-day mortality was used to define the survivor (n=26) and non-survivor (n=27) groups. Logistic regression identified mediators independently associated with mortality and SOFA score. Cytokine profiles in plasma and media were quantified by ELISA. Peripheral blood mononuclear cells (PBMCs) were isolated and treated with LPS, iMSC-EVs or both. Apoptosis, caspase-3 expression, and acute-phase markers (CRP, SAA) were assessed.

Increased age, cancer diagnosis and SOFA score were associated with mortality. Non-survivors exhibited significantly elevated IL-10, MCP-1, and IL-10/TNF-α ratio, with a lower IL-6/IL-10 ratio. IL-10 (OR = 1.12), MCP-1 (OR = 1.05), and IL-10/TNF-α ratio (OR = 6.61) independently predicted 60-day mortality. LPS-stimulated PBMCs from non-survivors showed a distinct pattern of cytokine responses compared to survivors. iMSC-EV treatment attenuated LPS-induced inflammation, reduced the IL-10/TNF-α ratio, decreased apoptosis and caspase-3 activation, and modulated CRP and SAA in a context-dependent manner.

Patient characteristics and cytokine levels were associated with 60-day sepsis mortality and reflect immunosuppression severity. iMSC-EVs exert immunomodulatory and cytoprotective effects on septic patient-derived PBMCs, supporting their potential as a cell-free therapeutic strategy for restoring immune homeostasis in sepsis.