Human umbilical cord mesenchymal stem cells derived exosome shuttling mir-129-5p attenuates inflammatory bowel disease by inhibiting ferroptosis

Journal of Nanobiotechnology

Research

Zhaoyang Zhang¹  Zhiping Wei²  Bo Wang²  Fei Mao²  Xu Zhang²  Dickson Kofi Wiredu Ocansey²  Sanhua Hang³ 

[1]Clinical Lab, Taicang Hospital of Traditional Chinese Medicine, 215400, Suzhou, Jiangsu, P.R. China

[2]Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, 212013, Zhenjiang, Jiangsu, P.R. China

[3]The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, 212300, Zhenjiang, Jiangsu, P.R. China

关键词: Mesenchymal stem cell-derived exosomes;    Ferroptosis;    miR-129-5p;    Inflammatory bowel disease;    ACSL4;    Lipid peroxidation;   

DOI  :  10.1186/s12951-023-01951-x

 received in 2023-01-13, accepted in 2023-06-02,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundFerroptosis, a unique form of non-apoptotic cell death, is dependent on iron and lipoperoxidation, and has been shown to be associated with the pathogenesis of inflammatory bowel disease (IBD). Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) are involved in cell survival, immune conditioning, and damage repair. However, the relationship between hucMSC-Ex, IBD, and ferroptosis is unknown. This paper explores the role of hucMSC-Ex in the repair of IBD through the regulation of the ferroptosis signaling pathway.ResultsIn this study, we used small RNA sequencing to find that miR-129-5p was highly expressed in hucMSC-Ex, and by predicting its targeting to ACSL4, we verified the effect of miR-129-5p on mice IBD in vitro and human colonic epithelial cells (HCoEpiC) in vivo. We found that miR-129-5p reduces ferroptosis in intestinal epithelial cells by targeting ACSL4 to repair IBD, which provides new strategies for the prevention and treatment of IBD.ConclusionIn conclusion, our results demonstrate that hucMSC-Ex relieves IBD by targeting ACSL4 with miR-129-5p to inhibit lipid peroxidation (LPO) and ferroptosis, reducing intestinal inflammation and repairing damages.Graphic abstractMechanism of hucMSC-Ex inhibiting ferroptosis in intestinal epithelial cells. System Xc− mediates the transport of extracellular cystine into the cell, which gets reduced to cysteine to participate in GSH-mediated metabolism. GPX4 strongly inhibits ferroptosis by helping scavenge reactive oxygen species. The depletion of GSH correlates with decreased GPX4, and the imbalance of the antioxidant system leads to the formation of toxic phospholipid hydroperoxide, which promotes the occurrence of ferroptosis with the participation of irons. HucMSC-Ex has the ability to relieve GSH and GPX4 depletion and repair the intracellular antioxidant system. Ferric ions enter the cytosol through DMT1 and participate in lipid peroxidation. HucMSC-Ex can reduce the expression of DMT1 and alleviate this process. HucMSC-Ex-derived miR-129-5p targets ACSL4 and reduces the expression of ACSL4, an enzyme that mediates the conversion of PUFAs into phospholipids in intestinal epithelial cells, and is a positive regulator of lipid peroxidation. Abbreviations: GSH, glutathione; GPX4, glutathione peroxidase 4; GSSG, oxidized glutathione; DMT1, divalent metal transporter 1; ACSL4, acyl-CoA synthetase long-chain family member 4; PUFAs, polyunsaturated fatty acids; ALOXs, lipoxygenases; CoA, coenzyme A; PL, phospholipid; PLOOH, hydroperoxides, LOH, phospholipid alcohols; LPO, lipid peroxidation.

【 授权许可】

CC BY   
© The Author(s) 2023

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