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

Abstract

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.

Extracellular Vesicles in Liver Transplantation: Current Evidence and Future Challenges

“…MSCs have garnered significant attention due to their unique characteristics and therapeutic possibilities [6]. In addition to their ability to differentiate into multiple cell types, MSCs also have potent anti-inflammatory and immunomodulatory effects that were already demonstrated in experimental models of LT [8]. However, the therapeutic effects of stem cells primarily result from the release of various paracrine factors, with EVs serving as key mediators.…”

“…Furthermore, MP is being increasingly investigated as a platform to allow interventions aiming at improving donor quality, including the possibility of administering stem cells or EVs during perfusion. By establishing an isolated ex situ platform in which the organ is metabolically active, therapies targeting IRI can be delivered directly to the liver, limiting systemic exposure to the recipient [8]. Indeed, the effectiveness of delivering MSCs during perfusion to mitigate IRI has been demonstrated across multiple organ systems [109][110][111].…”

“…Exosomes are smaller than microvesicles, typically measuring between 30-150 nm in diameter. Apoptotic cells release a third type of EV named apoptotic bodies [8].…”

“…In LT, EVs have emerged as promising biomarkers to assess the risk of decompensation in cirrhosis, improve early diagnosis of hepatocellular carcinoma (HCC) before and after LT, refine the diagnosis of allograft rejection, and monitor the adequacy of immunosuppression [14,15]. Furthermore, mesenchymal stem cells (MSCs) and EVs have been shown to mitigate IRI in experimental models and can be synergically applied with MP [8,11,[16][17][18].…”

Therapeutic potentials of mesenchymal stromal cells-derived extracellular vesicles in liver failure and marginal liver graft rehabilitation: a scoping review

“…These two studies highlighted the efficiency and feasibility of EVs infusion during NMP procedure, although no study has yet evaluated the impact of human MSC-EVs in an ex vivo perfused large animal or human liver NMP model. We still do not know whether MSC-EVs can rehabilitate marginal grafts, allowing some grafts to be recovered and reconditioned to be eligible for LT and/or to improve the function of other marginal grafts to improve recipients' outcomes 96 . This is a field of research that deserves to be explored in the coming years.…”