Single-cell transcriptomic analysis reveals therapeutic mechanisms of adipose-derived stem cell exosomes in...

Sepsis-induced acute lung injury remains a leading cause of mortality in critically ill patients, with limited effective treatments beyond supportive care. This study investigates the therapeutic efficacy and underlying mechanisms of adipose-derived stem cell (ADSC) exosomes on sepsis-induced lung injury and characterizes underlying cellular and molecular mechanisms.

We employed a cecal ligation and puncture (CLP) mouse model of sepsis and using male C57BL/6J mice ( Mus musculus , 8-10 weeks old) and administered ADSC-derived exosomes intravenously. Animals were randomly assigned to Sham, CLP, or CLP + ADSC-exosome groups. Survival rates ( n =12 for each group) and lung histopathology ( n =5 for each group) were assessed. Single-cell RNA sequencing was performed on lung tissues to analyze cell type-specific transcriptomic changes and intercellular communication networks ( n =2 for each group).

ADSC exosome treatment significantly improved survival rates and reduced lung pathology in CLP mice. Treatment altered lung cellular composition, increasing neutrophils, NKT cells, and monocytes while decreasing B and T cells. Gene expression analysis revealed downregulation of pro-inflammatory markers (TNF, IL-10, CCL3, and CCL4) and upregulation of tissue repair pathways. In neutrophils, exosomes reduced expression of respiratory burst genes while enhancing tissue repair mechanisms. In monocytes, treatment suppressed inflammatory cytokine production while promoting anti-inflammatory phenotypes. Exosome treatment is associated with transcriptomic changes suggestive of restored intercellular communication networks disrupted by sepsis, with increased signaling via CSF3, ANGPT, SPP1, and CCL pathways.

ADSC-derived exosomes effectively treat sepsis-induced lung injury by rebalancing the cellular environment and restoring homeostasis through modulation of immune cell function and intercellular communication, offering potential as a cell-free novel therapeutic approach for sepsis-related pulmonary complications.