Mesenchymal stem cell-derived exosome alleviates sepsis- associated acute liver injury by suppressing MALAT1 through microRNA-26a-5p: an innovative immunopharmacological intervention and therapeutic approach for sepsis

Jizhen Cai; Da Tang; Xiao Hao; Enyi Liu; Wenbo Li; Jian Shi

doi:10.3389/fimmu.2023.1157793

Mesenchymal stem cell-derived exosome alleviates sepsis- associated acute liver injury by suppressing MALAT1 through microRNA-26a-5p: an innovative immunopharmacological intervention and therapeutic approach for sepsis

Front Immunol. 2023 Jun 15:14:1157793. doi: 10.3389/fimmu.2023.1157793. eCollection 2023.

Authors

Jizhen Cai¹, Da Tang², Xiao Hao^{3

4}, Enyi Liu^{3

4}, Wenbo Li⁵, Jian Shi¹

Affiliations

¹ Department of Critical Care Medicine and Hematology, The Third Xiangya Hospital, Central South University, Changsha, China.
² Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.
³ Department of Hematology, Xiangya Hospital, Central South University, Changsha, China.
⁴ Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, China.
⁵ Department of Plastic and Aesthetic (Burn) Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.

Abstract

Background: Sepsis is a syndrome with the disturbed host response to severe infection and is a major health problem worldwide. As the front line of infection defense and drug metabolism, the liver is vulnerable to infection- or drug-induced injury. Acute liver injury (ALI) is thus common in patients with sepsis and is significantly associated with poor prognosis. However, there are still few targeted drugs for the treatment of this syndrome in clinics. Recent studies have reported that mesenchymal stem cells (MSCs) show potential for the treatment of various diseases, while the molecular mechanisms remain incompletely characterized.

Aims and methods: Herein, we used cecal ligation puncture (CLP) and lipopolysaccharide (LPS) plus D-galactosamine (D-gal) as sepsis-induced ALI models to investigate the roles and mechanisms of mesenchymal stem cells (MSCs) in the treatment of ALI in sepsis.

Results: We found that either MSCs or MSC-derived exosome significantly attenuated ALI and consequent death in sepsis. miR-26a-5p, a microRNA downregulated in septic mice, was replenished by MSC-derived exosome. Replenishment of miR-26a-5p protected against hepatocyte death and liver injury caused by sepsis through targeting Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), a long non-coding RNA highly presented in hepatocyte and liver under sepsis and inhibiting anti-oxidant system.

Conclusion: Taken together, the results of the current study revealed the beneficial effects of MSC, exosome or miR-26a-5p on ALI, and determined the potential mechanisms of ALI induced by sepsis. MALAT1 would be a novel target for drug development in the treatment of this syndrome.

Keywords: MALAT1; exosome; immune regulation; immunopharmacological interventions; mesenchymal stem cells; miR-26a-5p; sepsis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Exosomes* / metabolism
Liver / metabolism
Mesenchymal Stem Cells* / metabolism
Mice
MicroRNAs* / genetics
MicroRNAs* / metabolism
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Sepsis* / complications
Sepsis* / genetics
Sepsis* / therapy

Substances

MicroRNAs
RNA, Long Noncoding
Malat1 long non-coding RNA, mouse
Mirn26 microRNA, mouse

Grants and funding

This work was supported by Key Scientific Project of Hunan Province (2022SK2056), Natural Science Foundation of Hunan Province (2021JJ41006 &2022JJ30817), Postgraduate Research Innovation Project of Central South University (No.1053320191556) and Chen Xiao Ping Foundation of the Development of Science and Technology (CXPJJH12000009-102).