2. Academic Validation
  3. miR-29a-3p in Exosomes from Heme Oxygenase-1 Modified Bone Marrow Mesenchymal Stem Cells Alleviates Steatotic Liver Ischemia-Reperfusion Injury in Rats by Suppressing Ferroptosis via Iron Responsive Element Binding Protein 2

miR-29a-3p in Exosomes from Heme Oxygenase-1 Modified Bone Marrow Mesenchymal Stem Cells Alleviates Steatotic Liver Ischemia-Reperfusion Injury in Rats by Suppressing Ferroptosis via Iron Responsive Element Binding Protein 2

  • Oxid Med Cell Longev. 2022 Jun 9;2022:6520789. doi: 10.1155/2022/6520789.
Xiang Li 1,  Longlong Wu 2,  Xuan Tian 2,  Weiping Zheng 3 4,  Mengshu Yuan 1,  Xiaorong Tian 1,  Huaiwen Zuo 1,  Hongli Song 3 5,  Zhongyang Shen 3 6
Affiliations

Affiliations

  • 1 Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, China.
  • 2 School of Medicine, Nankai University, Tianjin, China.
  • 3 Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, China.
  • 4 NHC Key Laboratory of Critical Care Medicine, Tianjin 300192, China.
  • 5 Tianjin Key Laboratory of Organ Transplantation, Tianjin, China.
  • 6 Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
PMID: 35720183 DOI: 10.1155/2022/6520789
Abstract

Hepatic ischemia-reperfusion injury (IRI) is an inevitable result of liver surgery. Steatotic livers are extremely sensitive to IRI and have worse tolerance. Ferroptosis is considered to be one of the main factors of organ IRI. This study is aimed at exploring the role of Ferroptosis in the effect of heme oxygenase-1-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) on steatotic liver IRI and its mechanism. An IRI model of a steatotic liver and a hypoxia reoxygenation (HR) model of steatotic hepatocytes (SHPs) were established. Rat BMMSCs were extracted and transfected with the Ho1 gene to establish HO-1/BMMSCs, and their exosomes were extracted by ultracentrifugation. Ireb2 was knocked down to verify its role in Ferroptosis and cell injury in SHP-HR. Public database screening combined with quantitative real-time Reverse transcription PCR identified MicroRNAs (miRNAs) targeting Ireb2 in HO-1/BMMSCs exosomes. miR-29a-3p mimic and inhibitor were used for functional verification experiments. Liver function, histopathology, terminal deoxynulceotidyl transferase nick-end-labeling staining, cell viability, mitochondrial membrane potential, and cell death were measured to evaluate liver tissue and hepatocyte injury. Ferroptosis was assessed by detecting the levels of IREB2, Fe2+, malondialdehyde, glutathione, lipid Reactive Oxygen Species, Glutathione Peroxidase 4, prostaglandin-endoperoxide synthase 2 mRNA, and mitochondrial morphology. The results revealed that HO-1/BMMSCs improved liver tissue and hepatocyte injury and suppressed Ferroptosis in vivo and in vitro. The expression of IREB2 was increased in steatotic liver IRI and SHP-HR. Knocking down Ireb2 reduced the level of Fe2+ and inhibited Ferroptosis. HO-1/BMMSC exosomes reduced the expression of IREB2 and inhibited Ferroptosis and cell damage. Furthermore, we confirmed high levels of miR-29a-3p in HO-1/BMMSCs exosomes. Overexpression of miR-29a-3p downregulated the expression of Ireb2 and inhibited Ferroptosis. Downregulation of miR-29a-3p blocked the protective effect of HO-1/BMMSC exosomes on SHP-HR cell injury. In conclusion, Ferroptosis plays an important role in HO-1/BMMSC-mediated alleviation of steatotic liver IRI. HO-1/BMMSCs could suppress Ferroptosis by targeting Ireb2 via the exosomal transfer of miR-29a-3p.

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