Extracellular Vesicles as a Novel Therapeutic Option in Liver Transplantation

Longterm liver graft dysfunction and immunological rejection remain common adverse events, in part due to early acute rejection episodes initiated by ischemia/reperfusion injury (IRI) immediately following transplantation. Novel treatment methods are therefore required to ameliorate liver IRI and to promote longterm allograft acceptance. Extracellular vesicles (EVs) derived from tolerogenic phenotype cells may serve as a novel therapeutic option in liver transplantation due to their immunomodulatory and proregenerative effects. Studies of hepatic IRI along with animal liver allograft models have demonstrated that EVs isolated from mesenchymal stem/stromal cells, immature dendritic cells, and hepatocytes can reduce graft injury through mechanisms including enhancement of mitochondrial autophagy, inhibition of immune response, and promotion of tissue regeneration. These preclinical models may soon move translationally into clinical practice, necessitating the generation of robust methods to generate clinical-grade EVs. These methods must address issues of reproducibility and ability to scale up the tolerogenic cell cultivation, EV isolation, and EV characterization. Once generated, the efficient delivery of EVs to the donor organ prior to transplantation remains an issue that could be resolved through the novel organ storage method ex vivo machine perfusion (EVMP). In this review, we summarize studies that have used tolerogenic cell-derived EVs to ameliorate hepatic IRI and promote liver allograft acceptance, discuss the steps toward generation of clinical-grade EVs, and introduce EVMP as a novel method to efficiently deliver EVs.