Extracellular Vesicles Secreted by Human Adipose-derived Stem Cells (hASCs) Improve Survival Rate of Rats with Acute Liver Failure by Releasing lncRNA H19

Abstract

It has previously been reported that human adipose-derived stem cells (hASCs) can promote the regeneration of damaged tissues in rats with liver failure through a ‘paracrine effect’. Here we demonstrate a therapeutic effect of hASCs derived Extracellular Vesicles (EVs) on rat models with acute liver failure, as shown by the improvement of the survival rate by >70% compared to controls. Gene sequencing of rat liver revealed an increase in human long-chain non-coding RNA (lncRNA) H19 after hASC-derived EVs transplantation. When the H19 coding sequence was silenced in hASCs and EVs were then collected for treatment of rats with liver failure, we saw a decrease in the survival rate to 40%, compared to treatment with EVs generated from non-silenced hASCs. These data indicate that lncRNA H19 may be a potential therapeutic target for the treatment of liver failure.

Extracellular Vesicles in the Development of the Non-Alcoholic Fatty Liver Disease: An Update

“…In another hepatic injury study, the EVs from MSC exhibited protective effects on the hepatocytes despite being treated with liver injury stimulant drugs, partly via the upregulation of hepatocyte proliferation [74]. Other studies of EVs from the various origins of MSCs showed similar hepatic protective and regenerative effects, as seen in the bone-marrow-derived MSCs [75][76][77][78][79][80], human umbilical cord-derived MSCs [81][82][83], human liver stem cells [84,85], induced pluripotent stem cell-derived MSCs [86], human embryonic-derived MSCs [64], human menstrual blood-derived MSCs [87], and adipose-derived MSCs [88][89][90][91]. As for the prevention of fibrosis via the suppression of HSCs, a study of EVs from the chorionic plate-derived MSCs showed that these EVs suppressed the activation and proliferation of HSCs due to the presence of miR-125b in the cargo, thus preventing liver fibrosis [92].…”

Therapeutic potential of extracellular vesicle‐associated long noncoding RNA

“…Additionally, EVs have also been loaded with lncRNA by manipulation of cellular lncRNA content. Overexpression of cellular lncRNA stoichiometrically favors loading of EVs with that particular lncRNA (Figure 4, bottom right), as demonstrated by Jin et al 57 This approach has been also been modified for the creation of EV-mimetics via extrusion of lncRNA-overexpressing cells (Figure 4, bottom left). Creation of mimetics in this manner results in high vesicle yields, 108 although it is unclear if the favorable physiological properties of EVs would be retained via this approach, and reproducibility and scalability also present challenges.…”

“…Jin et al showed that EVs derived from human adipose MSCs reduced the amount of liver damage in an in vivo murine acute liver failure model via delivery of lncRNA H19. When H19 was silenced in MSCs, EV efficacy dropped significantly 57 . Liver fibrosis is also associated with a high death rate, and reducing scaring of the liver is important in developing a treatment.…”

Extracellular Vesicles: A Therapeutic Option for Liver Fibrosis

“…Long-chain non coding (lncRNA) H19 shuttled by EVs was found to be involved in the pro-regenerative effect of ASC-EVs. In fact, EVs obtained from silenced ASCs for lncRNA H19 did not improve survival [85]. The immune-suppressive effect of EVs was also demonstrated on a murine hepatic injury model induced by concanavalin A (con-A), a lectin derived from jack beans.…”