Ex Vivo Normothermic Hypoxic Rat Liver Perfusion Model: An Experimental Setting for Organ Recondition and Pharmacological Intervention

Rigo, Federica; Navarro-Tableros, Víctor; Stefano, Nicola De; Calleri, Alberto; Romagnoli, Renato

doi:10.1007/978-1-0716-1225-5_10

Cited by 4 publications

(5 citation statements)

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“…This method keeps the graft metabolically active, allowing to assess the organ quality, and gives the opportunity to pharmacologically treat the livers with the aim of further improving sub-optimal organs [14,15]. In particular, NMP has recently become a promising candidate for stem cell and stem cellderived therapies, as it offers the possibility to monitor their liver-specific delivery and to maximize their therapeutic activity [16,27,28,44]. HLSCs are stem cells resident in the hepatic parenchyma with regenerative and hepatoprotective properties [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, in a model of hypoxic liver reconditioning by NMP, we have shown that administered HLSC‐EVs were able to localize into the hepatic parenchyma within 4 h of perfusion. The livers subjected to hypoxia during NMP benefited from treatment with HLSC‐EV, reducing the release of AST and LDH and showing a significant reduction in apoptosis and necrosis [ 27 , 28 ]. Moreover, similar protective effects on cytolysis and histology were observed in another recent work by our group, in which HLSC‐EVs were systemically administered in a mouse model of partial liver IRI.…”

Section: Introductionmentioning

confidence: 99%

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Human liver stem cell‐derived extracellular vesicles reduce injury in a model of normothermic machine perfusion of rat livers previously exposed to a prolonged warm ischemia

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human liver stem cell‐derived extracellular vesicles reduce injury in a model of normothermic machine perfusion of rat livers previously exposed to a prolonged warm ischemia

et al. 2021

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“…disease specific biomarkers. Currently, there are several examples of using machine perfusion platforms to study organ reconditioning, pharmacological interventions to prevent ischemia-reperfusion injury, defatting steatotic livers or studying the effect of oncolytics (43)(44)(45)(46)(47). Recent studies have adapted machine perfusion to demonstrate the possibility to prolong organ perfusion duration (48)(49)(50), with perfusion of human and porcine livers for up to 7 days (18).…”

Section: Discussionmentioning

confidence: 99%

Normothermic perfusion of cirrhotic and non-cirrhotic explanted human livers: applicability to study drug pharmacokinetics

Stevens

Dubbeld

Doppenberg

et al. 2022

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Background and Purpose: Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can be used to investigate hepatic first-pass, clearance, biliary excretion and drug-drug interactions. Experimental approach: Eleven livers were included in the study, seven with a cirrhotic and four with a non-cirrhotic disease background. After explantation of the diseased liver, the liver artery and portal vein were reconstructed followed by NMP. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin and furosemide) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with drug inhibitors to study relevant drug-drug interactions. Key results: The explanted livers showed good viability and functionality after explantation and 360 minutes of NMP. Hepatic first-pass and clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in Cmax of 10.03 and 2.89 times, respectively, compared to non-cirrhotic livers. No major differences were observed for metformin and furosemide. Drug-drug interaction of rosuvastatin or digoxin with inhibitors were more pronounced in non-cirrhotic livers compared to cirrhotic livers. Conclusions and Implications: Our results demonstrated that explanted cirrhotic and non-cirrhotic livers were suitable for NMP and we demonstrated the applicability to study hepatic first pass, clearance, biliary excretion and drug-drug interaction. This model can be applied in a variety of research settings for hepatology, transplantation and pharmacology

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“…Compared to stem cell-based treatments, EVs could be advantageous in terms of genetic stability, storage conditions and administration route, also during dynamic preservation, where the potential detrimental effects that NMP components may have on cellular membranes could be avoided using cell-free approaches [89,90]. In a model of hypoxic liver NMP, our group has demonstrated the feasibility of delivering EVs to hepatocytes during NMP [91,92]. HLSC-EV were administrated at perfusion start and were detected in the hepatocytes after 4 h of NMP, as confirmed by epifluorescence microscopy.…”

Section: Current Application Of Mscs and Derived Products During Mach...mentioning

confidence: 99%

State-of-the-Art and Future Directions in Organ Regeneration with Mesenchymal Stem Cells and Derived Products during Dynamic Liver Preservation

et al. 2022

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Transplantation is currently the treatment of choice for end-stage liver diseases but is burdened by the shortage of donor organs. Livers from so-called extended-criteria donors represent a valid option to overcome organ shortage, but they are at risk for severe post-operative complications, especially when preserved with conventional static cold storage. Machine perfusion technology reduces ischemia-reperfusion injury and allows viability assessment of these organs, limiting their discard rate and improving short- and long-term outcomes after transplantation. Moreover, by keeping the graft metabolically active, the normothermic preservation technique guarantees a unique platform to administer regenerative therapies ex vivo. With their anti-inflammatory and immunomodulatory properties, mesenchymal stem cells are among the most promising sources of therapies for acute and chronic liver failure, but their routine clinical application is limited by several biosafety concerns. It is emerging that dynamic preservation and stem cell therapy may supplement each other if combined, as machine perfusion can be used to deliver stem cells to highly injured grafts, avoiding potential systemic side effects. The aim of this narrative review is to provide a comprehensive overview on liver preservation techniques and mesenchymal stem cell-based therapies, focusing on their application in liver graft reconditioning.

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Ex Vivo Normothermic Hypoxic Rat Liver Perfusion Model: An Experimental Setting for Organ Recondition and Pharmacological Intervention

Cited by 4 publications

References 10 publications

Human liver stem cell‐derived extracellular vesicles reduce injury in a model of normothermic machine perfusion of rat livers previously exposed to a prolonged warm ischemia

Human liver stem cell‐derived extracellular vesicles reduce injury in a model of normothermic machine perfusion of rat livers previously exposed to a prolonged warm ischemia

Normothermic perfusion of cirrhotic and non-cirrhotic explanted human livers: applicability to study drug pharmacokinetics

State-of-the-Art and Future Directions in Organ Regeneration with Mesenchymal Stem Cells and Derived Products during Dynamic Liver Preservation

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