Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury

Abstract

Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate liver injury. Here, the protective effect of MSCs on carbon tetrachloride (CCl4)-induced acute liver injury (ALI) was investigated. In this study, we illustrated a novel mechanism that ferroptosis, a newly recognized form of regulated cell death, contributed to CCl4-induced ALI. Subsequently, based on the in vitro and in vivo evidence that MSCs and MSC-derived exosomes (MSC-Exo) treatment achieved pathological remission and inhibited the production of lipid peroxidation, we proposed an MSC-based therapy for CCl4-induced ALI. More intriguingly, treatment with MSCs and MSC-Exo downregulated the mRNA level of prostaglandin-endoperoxide synthase 2 (Ptgs2) and lipoxygenases (LOXs) while it restored the protein level of SLC7A11 in primary hepatocytes and mouse liver, indicating that the inhibition of ferroptosis partly accounted for the protective effect of MSCs and MSC-Exo on ALI. We further revealed that MSC-Exo-induced expression of SLC7A11 protein was accompanied by increasing of CD44 and OTUB1. The aberrant expression of ubiquitinated SLC7A11 triggered by CCl4 could be rescued with OTUB1-mediated deubiquitination, thus strengthening SLC7A11 stability and thereby leading to the activation of system XC− to prevent CCl4-induced hepatocyte ferroptosis. In conclusion, we showed that MSC-Exo had a protective role against ferroptosis by maintaining SLC7A11 function, thus proposing a novel therapeutic strategy for ferroptosis-induced ALI.

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

“…Considerable evidence has suggested that exosomes have important roles not only in the pathogenic progression of chronic liver disease but also in the initial onset of acute liver injury. [113][114][115] HSC-derived exosomes are considered to be one of the most prominent indicators of the degree of liver damage, 21 which is supported by a series of experimental studies. To date, most investigations of HSC-derived exosomes on liver damage have focused on chronic liver injury and persisting consequences that result in acute liver injury.…”

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

“…Tan et al proved that MSC-exos may promote xCT/GPX4-mediated activated hepatic stellate cells ferroptosis through the delivery of BECN1 [ 65 ]. Lin et al also concluded that MSC-exos might alleviate ferroptosis via the CD44 and OTUB1-mediated stabilization of SLC7A11 [ 66 ]. Therefore, we speculated that ERC-exos regulates ferroptosis primarily through delivering its rich proteins and miRNA.…”

“…Ferroptosis is involved in the progression of numerous diseases, and it has been proved that MSC-exos could attenuate diseases through inhibiting ferroptosis. Studies have found that MSC-exos could deliver its miRNA and proteins that act on genes participating in iron metabolism and lipid peroxide process to regulate [66]. Therefore, we speculated that ERC-exos regulates ferroptosis primarily through delivering its rich proteins and miRNA.…”

The Regulatory Role of Ferroptosis in Bone Homeostasis

“…For example, it was recently shown that MSCs are capable of inhibiting the production of lipid peroxidation and alleviating ferroptosis both in vitro and in vivo . The authors also demonstrated that MSC-derived exosomes are involved in the underlying mechanisms of the effect of MSCs on ferroptosis, which could significantly downregulate the expression of prostaglandin-endoperoxide synthase 2 and promote SLC7A11 expression [ 38 ]. Similarly, the suppressive effect of MSCs on ferroptosis was seen in neuronal cells [ 39 ].…”