Single-cell transcriptomic analysis reveals therapeutic mechanisms of adipose-derived stem cell exosomes in sepsis-induced lung injury

Shao-Chun Wu; Cheng-Shyuan Rau; Yi-Chan Wu; Chia-Wei Lin; Tsu-Hsiang Lu; Chia-Wen Tsai; Ming-Yu Yang; Ching-Hua Hsieh

doi:10.1097/JS9.0000000000002894

Single-cell transcriptomic analysis reveals therapeutic mechanisms of adipose-derived stem cell exosomes in sepsis-induced lung injury

Int J Surg. 2025 Jul 2. doi: 10.1097/JS9.0000000000002894. Online ahead of print.

Authors

Shao-Chun Wu^{1

2}, Cheng-Shyuan Rau³, Yi-Chan Wu⁴, Chia-Wei Lin⁴, Tsu-Hsiang Lu⁴, Chia-Wen Tsai⁴, Ming-Yu Yang², Ching-Hua Hsieh⁴

Affiliations

¹ Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan.
² Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
³ Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan.
⁴ Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan.

PMID: 40607951
DOI: 10.1097/JS9.0000000000002894

Abstract

Background: Sepsis-induced acute lung injury (ALI) 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 characterize underlying cellular and molecular mechanisms.

Methods: We employed a cecal ligation and puncture (CLP) mouse model of sepsis and using male C57BL/6 J 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).

Results: 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, 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.

Conclusion: 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.

Keywords: acute lung injury; adipose-derived stem cells; exosomes; sepsis; single-cell RNA sequencing (scRNA-seq).