Endometrial Regenerative Cell-Derived Exosomes Attenuate Experimental Colitis through Downregulation of Intestine Ferroptosis

Abstract

Background. Endometrial regenerative cells (ERCs) have been identified to ameliorate colitis in mice; however, whether exosomes derived from ERCs (ERC-exos) own similar effects on colitis remains unclear. Ferroptosis, an iron-dependent cell programmed death form, has been reported to promote inflammation in UC. Thus, in this study, whether ERC-exos can treat colitis and regulate intestine ferroptosis will be explored. Methods. In this study, iron, malondialdehyde (MDA) production, glutathione (GSH) synthesis, and acyl-CoA synthetase long-chain family member (ACSL) 4 and glutathione peroxidase 4 (GPX4) expressions were measured in colon samples from healthy people and UC patients to explore the effects of ferroptosis. In vitro, ERC-exos were cocultured with ferroptosis inducer erastin-treated NCM460 human intestinal epithelial cell line, and ferroptotic parameters were measured. In vivo, colitis was induced by 3% dextran sulfate sodium (DSS) in BALB/c mice, and animals were randomly assigned to normal, untreated, and ERC-exos-treated groups. The Disease Activity Index (DAI) score, histological features, tissue iron, MDA, GSH, ACSL4, and GPX4 were measured to verify the role of ERC-exos in attenuating UC. Results. Compared with healthy people, UC samples exhibited higher levels of iron, MDA, and ACSL4, while less levels of GSH and GPX4. In vitro, the CCK-8 assay showed that ERC-exos rescued erastin-induced cell death, and ERC-exos treatment significantly increased the levels of GSH and expression of GPX4, while markedly decreasing the levels of iron, MDA, and expression of ACSL4. In vivo, ERC-exos treatment effectively reduced DAI score, ameliorated colon pathological damage, and improved disease symptoms. Moreover, ERC-exos treatment further enhanced the levels of GSH and the expression of GPX4 but reduced the levels of iron, MDA, and expression of ACSL4 in the colon of colitis mice. Conclusions. Ferroptosis was involved in the pathogenesis of UC, and ERC-exos attenuated DSS-induced colitis through downregulating intestine ferroptosis. This study may provide a novel insight into treating UC in the future.

Chondroprotective effects of bone marrow mesenchymal stem cell- derived exosomes in osteoarthritis

“…Partially in line with these results, our study revealed that in the IL-1β-stimulated rat chondrocytes, cell viability was suppressed, Fe 2+ , ROS and MDA levels were elevated, while GSH levels were declined; conversely, these changes were neutralized by BMSC-Exos, thus suggesting that BMSC-Exos could hinder the IL-1β-induced chondrocyte ferroptosis. A previous report has also indicated that Exos derived from endometrial regenerative cells can enhance the levels of GSH but reduced the levels of iron, and MDA in the colon of colitis mice, thus down-regulating intestine ferroptosis and attenuating dextran sulfate sodium-induced colitis [33]. Moreover, BMSC-Exos have demonstrated protective effects on podocytes against ferroptosis induced by HBx overexpression by transferring miR-223-3p [34].…”

Novel Canthin-6-one Derivatives: Design, Synthesis, and Their Antiproliferative Activities via Inducing Apoptosis, Deoxyribonucleic Acid Damage, and Ferroptosis

“…HT29 cells were pretreated with or without ferrostatin-1 (1.0 μM) for 4 h and then treated with CO (5.0 μM) or 8h (1.0 or 5.0 μM) to detect lipid peroxidation levels. Also, an MDA assay kit (S0131S, Shanghai Titan) was used to determine the levels of MDA …”

“…Also, an MDA assay kit (S0131S, Shanghai Titan) was used to determine the levels of MDA. 46 4.10. Western Blot Analysis.…”

The role of extracellular vesicles in iron homeostasis and ferroptosis: Focus on musculoskeletal diseases

“…For example, Zhang et al demonstrated that exosomes containing microsomal triglyceride transfer protein could decrease the lipid ROS level of cancer cells via regulating glutathione peroxidase 4 (GPX4) and SLC7A11 127 . EVs derived from MSCs or other progenitor cells could also induce the expression of GPX4, SLC7A11 and glutathione, thereby activating endogenous anti‐oxidative signaling pathway, 128–130 which endows the EVs with anti‐ferroptosis ability. Moreover, other signaling pathways including P62‐associated autophagy, ferritinophagy, or NRF2 pathway may also be involved in EV‐mediated ferroptosis suppression 131,132 .…”

“…T A B L E 1 EVs effects on the fate of cell ferroptosis. 127 EVs derived from MSCs or other progenitor cells could also induce the expression of GPX4, SLC7A11 and glutathione, thereby activating endogenous anti-oxidative signaling pathway, [128][129][130] which endows the EVs with anti-ferroptosis ability.…”