Journal
MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume -, Issue -, Pages -Publisher
SPRINGER
DOI: 10.1007/s11010-023-04770-8
Keywords
Exosome; Mesenchymal stem cell; Ferroptosis; Liver transplantation
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Exosomes derived from heme oxygenase 1-modified bone marrow mesenchymal stem cells (HExos) can attenuate ferroptosis and protect biliary tracts from ischemia reperfusion injury (IRI) in a rat fatty liver transplantation model. HExos deliver miR-204-5p to negatively regulate ferroptosis and protect steatotic grafts, indicating their potential as a strategy to prevent biliary IRI.
Fatty liver grafts are susceptible to ischemia reperfusion injury (IRI), increasing the risk of biliary complications after liver transplantation (LT). Ferroptosis, a newly recognized programmed cell death, is expected to be a novel therapeutic target for IRI. We investigated whether exosomes derived from heme oxygenase 1-modified bone marrow mesenchymal stem cells (HExos) relieve ferroptosis and protect biliary tracts from IRI in a rat fatty liver transplantation model. Rats were fed with a methionine choline deficient (MCD) diet for 2 weeks to induce severe hepatic steatosis. Steatotic grafts were implanted and HExos were administered after liver transplantation. A series of functional assays and pathological analysis were performed to assess ferroptosis and biliary IRI. The HExos attenuated IRI following liver transplantation, as demonstrated by less ferroptosis, improved liver function, less Kupffer and T cell activation, and less long-term biliary fibrosis. MicroRNA (miR)-204-5p delivered by HExos negatively regulated ferroptosis by targeting a key pro-ferroptosis enzyme, ACSL4. Ferroptosis contributes to biliary IRI in fatty liver transplantation. HExos protect steatotic grafts by inhibiting ferroptosis, and may become a promising strategy to prevent biliary IRI and expand the donor pool.
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