2. Academic Validation
  3. miR-124-3p delivered by exosomes from heme oxygenase-1 modified bone marrow mesenchymal stem cells inhibits ferroptosis to attenuate ischemia-reperfusion injury in steatotic grafts

miR-124-3p delivered by exosomes from heme oxygenase-1 modified bone marrow mesenchymal stem cells inhibits ferroptosis to attenuate ischemia-reperfusion injury in steatotic grafts

  • J Nanobiotechnology. 2022 Apr 22;20(1):196. doi: 10.1186/s12951-022-01407-8.
Longlong Wu 1,  Xuan Tian 1,  Huaiwen Zuo 2,  Weiping Zheng 3 4,  Xiang Li 2,  Mengshu Yuan 2,  Xiaorong Tian 2,  Hongli Song 5 6
Affiliations

Affiliations

  • 1 School of Medicine, Nankai University, Tianjin, People's Republic of China.
  • 2 Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
  • 3 Department of Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China.
  • 4 NHC Key Laboratory of Critical Care Medicine, Tianjin, 300192, People's Republic of China.
  • 5 Department of Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China. [email protected].
  • 6 Tianjin Key Laboratory of Organ Transplantation, Tianjin, People's Republic of China. [email protected].
PMID: 35459211 DOI: 10.1186/s12951-022-01407-8
Abstract

Background: Steatotic livers tolerate ischemia-reperfusion injury (IRI) poorly, increasing the risk of organ dysfunction. Ferroptosis is considered the initiating factor of organ IRI. Heme oxygenase oxygen-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) (HO-1/BMMSCs) can reduce hepatic IRI; however, the role of Ferroptosis in IRI of steatotic grafts and the effect of HO-1/BMMSCs-derived exosomes (HM-exos) on Ferroptosis remain unknown.

Methods: A model of rat liver transplantation (LT) with a severe steatotic donor liver and a model of hypoxia and reoxygenation (H/R) of steatotic hepatocytes were established. Exosomes were obtained by differential centrifugation, and the differentially expressed genes (DEGs) in liver after HM-exo treatment were detected using RNA sequencing. The expression of Ferroptosis markers was analyzed. MicroRNA (miRNA) sequencing was used to analyze the miRNA profiles in HM-exos.

Results: We verified the effect of a candidate miRNA on Ferroptosis of H/R treated hepatocytes, and observed the effect of exosomes knockout of the candidate miRNA on hepatocytes Ferroptosis. In vitro, HM-exo treatment reduced the IRI in steatotic grafts, and enrichment analysis of DEGs suggested that HM-exos were involved in the regulation of the Ferroptosis pathway. In vitro, inhibition of Ferroptosis by HM-exos reduced hepatocyte injury. HM-exos contained more abundant miR-124-3p, which reduced Ferroptosis of H/R-treated cells by inhibiting prostate six transmembrane epithelial antigen 3 (STEAP3), while overexpression of Steap3 reversed the effect of mir-124-3p. In addition, HM-exos from cell knocked out for miR-124-3p showed a weakened inhibitory effect on Ferroptosis. Similarly, HM-exo treatment increased the content of miR-124-3p in grafts, while decreasing the level of STEAP3 and reducing the degree of hepatic Ferroptosis.

Conclusion: Ferroptosis is involved in the IRI during LT with a severe steatotic donor liver. miR-124-3p in HM-exos downregulates Steap3 expression to inhibit Ferroptosis, thereby attenuating graft IRI, which might be a promising strategy to treat IRI in steatotic grafts.

Keywords

Bone marrow mesenchymal stem cells; Exosomes; Ferroptosis; Heme oxygenase oxygen-1; Ischemia–reperfusion injury; Liver transplantation; STEAP3; miR-124-3p.

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