Summary Livers from donors after circulatory death (DCD) are a promising option to increase the donor pool, but their use is associated with higher complication rate and inferior graft survival. Normothermic machine perfusion (NMP) keeps the graft at 37°C, providing nutrients and oxygen supply. Human liver stem cell‐derived extracellular vesicles (HLSC‐EVs) are able to reduce liver injury and promote regeneration. We investigated the efficacy of a reconditioning strategy with HLSC‐EVs in an experimental model of NMP. Following total hepatectomy, rat livers were divided into 4 groups: (i) healthy livers, (ii) warm ischemic livers (60 min of warm ischemia), (iii) warm ischemic livers treated with 5 × 108 HLSC‐EVs/g‐liver, and (iv) warm ischemic livers treated with a 25 × 108 HLSC‐EVs/g‐liver. NMP lasted 6 h and HLSC‐EVs (Unicyte AG, Germany) were administered within the first 15 min. Compared to controls, HLSC‐EV treatment significantly reduced transaminases release. Moreover, HLSC‐EVs enhanced liver metabolism by promoting phosphate utilization and pH self‐regulation. As compared to controls, the higher dose of HLSC‐EV was associated with significantly higher bile production and lower intrahepatic resistance. Histologically, this group showed reduced necrosis and enhanced proliferation. In conclusion, HLSC‐EV treatment during NMP was feasible and effective in reducing injury in a DCD model with prolonged warm ischemia.

Hepatic ischemia-reperfusion injury (IRI) is observed in liver transplantation and hepato-biliary surgery and is associated with an inflammatory response. Human liver stem cell-derived extracellular vesicles (HLSC-EV) have been demonstrated to reduce liver damage in different experimental settings by accelerating regeneration and by modulating inflammation. The aim of the present study was to investigate whether HLSC-EV may protect liver from IRI in a mouse experimental model. Segmental IRI was obtained by selective clamping of intrahepatic pedicles for 90 min followed by 6 h of reperfusion. HLSC-EV were administered intravenously at the end of the ischemic period and histopathological and biochemical alterations were evaluated in comparison with controls injected with vehicle alone. Intra liver localization of labeled HLSC-EV was assessed by in in vivo Imaging System (IVIS) and the internalization into hepatocytes was confirmed by fluorescence analyses. As compared to the control group, administration of 3 × 109 particles (EV1 group) significantly reduced alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) release, necrosis extension and cytokines expression (TNF-α, CCL-2 and CXCL-10). However, the administration of an increased dose of HLSC-EV (7.5 × 109 particles, EV2 group) showed no significant improvement in respect to controls at enzyme and histology levels, despite a significantly lower cytokine expression. In conclusion, this study demonstrated that 3 × 109 HLSC-EV were able to modulate hepatic IRI by preserving tissue integrity and by reducing transaminases release and inflammatory cytokines expression. By contrast, a higher dose was ineffective suggesting a restricted window of biological activity.

Chronic liver disease increased the risk of severe coronavirus disease 2019 (COVID‐19). Trials to assess efficacy/safety of COVID‐19 vaccines in liver disease are underway. We evaluated the humoral immune response and safety of anti–COVID‐19 vaccination among patients waiting liver transplantation (LT). We enrolled all pre‐LT adults who completed anti‐COVID‐19 vaccination between January 2021‐August 2021 as study group. Patients with histories of COVID‐19 received 1 vaccine dose, and all others received 2 doses. Patients were tested for COVID‐19 immunoglobulin G (IgG) within 1 and 2 months after vaccination. Safety was evaluated with telephone interviews/outpatient visits. A control group of 30 healthcare workers who underwent vaccination in January 2021 and tested for IgG after 4 months was included. In the 89 pre‐LT patients, at T1 (23 days after vaccination), seroconversion rate was 94.4%, and median IgG value was 1980 binding antibody units/mL (interquartile range 646‐2080), and at T2 (68 days after vaccination) was 92.0%, with IgG value of 1450 (577‐2080); (T1 versus T2, P = 0.38). In the 10/89 patients who received 1 vaccine dose, the median IgG value was 274 (68‐548) before vaccine (T0), 2080 (1165‐2080) at T1, and 2030 (964‐2080) at T2 (T0 versus T1, P = 0.03; T1 versus T2, P = 0.99). All controls tested positive at 4 months after vaccination, with a median value of 847 (509‐1165; P < 0.001 versus T1 and P = 0.04 versus T2 in the study group). No serious adverse event was reported in both groups. Our data from 89 pre‐LT patients suggest a high rate of immunization (94.4%) after a median time of 23 days from safe COVID‐19 vaccine. None of the patients developed COVID‐19.

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