Exosomal miR-218 secreted from endothelial progenitor cells mitigates acute lung injury in sepsis mice by inhibiting HMGA1 in alveolar macrophages

  • Stem Cell Res Ther. 2025 Aug 6;16(1):431. doi: 10.1186/s13287-025-04558-1.
Guibin Liang  #  1  2  3 ,  Menghao Zeng  #  1  2  3 ,  Qianlu Wang  1 ,  Wenhua Wang  1 ,  Jie Liu  1 ,  Min Gao  1 ,  Zhihui He  4  5  6
Affiliations
  • 1. Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
  • 2. Sepsis Translational Medicine Key Laboratory of Hunan Province, Changsha, Hunan, China.
  • 3. National Engineering Research Center for Human Stem Cells, Changsha, Hunan, China.
  • 4. Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. [email protected].
  • 5. Sepsis Translational Medicine Key Laboratory of Hunan Province, Changsha, Hunan, China. [email protected].
  • 6. National Engineering Research Center for Human Stem Cells, Changsha, Hunan, China. [email protected].
  • # Contributed equally.
PMID: 40770661 DOI: 10.1186/s13287-025-04558-1
Abstract

Background and objective: Sepsis-related acute lung injury (S-ALI) had become an important public health issue worldwide. However, the mechanism of S-ALI was still not fully understood. This study aims to investigate the possibility of exosomes secreted from endothelial progenitor cells (EPCs) serving as a carrier for MicroRNA (miR)-218 to alleviate S-ALI and explore the possible mechanism.

Methods: Exosomes were isolated from EPCs of C57BL/6J mice using differential centrifugation. Exosomes tracking in vivo and their uptake by EPCs in vitro were detected. miR-218 inhibitor and mimic were applied to investigate its function in mice and regulating polarization of alveolar macrophages (AMs). Bioinformatics and dual-luciferase reporter gene assays were used to explore the downstream targets of miR-218. si-HMGA1 and oe-HMGA1 were used to investigate its function in regulating polarization of AMs. Rescue experiments were carried out to uncover the interaction between miR-218 and HMGA1 in AMs.

Results: Exosomes were isolated from EPCs and confirmed their accumulation in the mice lung as well as their uptake by AMs in vitro. In vivo, miR-218 transferred by exosomes secreted from EPCs mitigated ALI. In vitro, miR-218 inhibitor enhanced LPS-induced polarization of M1 macrophages, while miR-218 mimic suppressed these reactions. HMGA1 was confirmed as a target gene of miR-218, and its over-expression offset the protective effects of miR-218.

Conclusions: miR-218 transferred by exosomes secreted from EPCs mitigated ALI in septic mice by inhibiting HMHA1 which regulates macrophages polarization.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13287-025-04558-1.

Keywords
Alveolar macrophage; Endothelial progenitor cells; MicroRNA-218; Polarization; Sepsis.
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