First Report on Ex Vivo Delivery of Paracrine Active Human Mesenchymal Stromal Cells to Liver Grafts During Machine Perfusion

Verstegen, Monique M A; Mezzanotte, Laura; Ridwan, R.Y.; Wang, Kairong; Haan, Jubi de; Schurink, Ivo J.; Sierra-Parraga, Jesus Maria; Hoogduijn, Martin J.; Kessler, Benedikt M.; Huang, Honglei; Hall, Sean; IJzermans, Jan N.M.; Löwik, Clemens W.G.M.; Laan, Luc J. W. van der; Jonge, Jeroen de

doi:10.1097/tp.0000000000002986

Cited by 27 publications

(24 citation statements)

References 4 publications

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“…Novel therapeutic strategies like ex vivo perfusion are already augmenting the pool of transplantable organs ( 164 ). Organ reconditioning strategies have already been applied in animal models to reduce the ischemia reperfusion injury by the infusion of MSCs or other anti-inflammatory agents ( 165 ) or to reduce steatosis using defatting agents before transplantation ( 166 ). Organ machine perfusion opens the door to a different approach to try to induce the tolerance by the infusion of tolerogenic molecules or treating the graft by immunomodulatory cells prior to implantation in the donor.…”

Section: Future Therapeutic Strategies To Induce Long Term Tolerancementioning

confidence: 99%

The Immunological Basis of Liver Allograft Rejection

et al. 2020

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Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.

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Section: Future Therapeutic Strategies To Induce Long Term Tolerancementioning

confidence: 99%

The Immunological Basis of Liver Allograft Rejection

et al. 2020

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“…MSC represent a potential therapy to enhance the regeneration of donor liver tissue. Proof of concept for delivery of MSC during machine perfusion has recently been published paving the way for further study (105). MSC appear to be retained in the perfused liver and are still able to exert paracrine effects on liver tissue, similar findings have been demonstrated in porcine renal perfusion systems (106,107).…”

Section: Therapeutic Strategies Utilizing Msc In Liver Transplantationmentioning

confidence: 74%

Mesenchymal Stromal Cells, a New Player in Reducing Complications From Liver Transplantation?

Owen

Newsome

2020

Front. Immunol.

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In response to the global burden of liver disease there has been a commensurate increase in the demand for liver transplantation. However, due to a paucity of donor organs many centers have moved toward the routine use of marginal allografts, which can be associated with a greater risk of complications and poorer clinical outcomes. Mesenchymal stromal cells (MSC) are a multi-potent progenitor cell population that have been utilized to modulate aberrant immune responses in acute and chronic inflammatory conditions. MSC exert an immunomodulatory effect on innate and adaptive immune systems through the release of both paracrine soluble factors and extracellular vesicles. Through these routes MSC can switch the regulatory function of the immune system through effects on macrophages and T regulatory cells enabling a switch of phenotype from injury to restoration. A key benefit seems to be their ability to tailor their response to the inflammatory environment without compromising the host ability to fight infection. With over 200 clinical trials registered to examine MSC therapy in liver disease and an increasing number of trials of MSC therapy in solid organ transplant recipients, there is increasing consideration for their use in liver transplantation. In this review we critically appraise the potential role of MSC therapy in the context of liver transplantation, including their ability to modulate reperfusion injury, their role in the reduction of medium term complications in the biliary tree and their potential to enhance tolerance in transplanted organs.

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“…Plasma levels of pro-inflammatory cytokines IL-6, IL-8 and TNF-α and anti-inflammatory TGF-β also remained unaffected by MSC transplantation in our study, highlighting the questionable ability of MSC to modulate immune response upon injection into liver, where the cooperation of immune cells and MSC is still a matter for debate. Even though MSC has the potential to be delivered to the liver [ 31 ], a possible explanation for this result is that MSC can be phagocytosed and eliminated by activated monocytes [ 32 ]. In the liver, resident Kupffer cells can interact with injected MSC and switch into anti-inflammatory and anti-fibrotic stages, but this has only been shown in vitro or in rodent models [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stromal Cell Therapy in Novel Porcine Model of Diffuse Liver Damage Induced by Repeated Biliary Obstruction

Vištějnová

Liška

Kumar

et al. 2021

IJMS

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In liver surgery, biliary obstruction can lead to secondary biliary cirrhosis, a life-threatening disease with liver transplantation as the only curative treatment option. Mesenchymal stromal cells (MSC) have been shown to improve liver function in both acute and chronic liver disease models. This study evaluated the effect of allogenic MSC transplantation in a large animal model of repeated biliary obstruction followed by partial hepatectomy. MSC transplantation supported the growth of regenerated liver tissue after 14 days (MSC group, n = 10: from 1087 ± 108 (0 h) to 1243 ± 92 mL (14 days); control group, n = 11: from 1080 ± 95 (0 h) to 1100 ± 105 mL (14 days), p = 0.016), with a lower volume fraction of hepatocytes in regenerated liver tissue compared to resected liver tissue (59.5 ± 10.2% vs. 70.2 ± 5.6%, p < 0.05). Volume fraction of connective tissue, blood vessels and bile vessels in regenerated liver tissue, serum levels of liver enzymes (AST, ALT, ALP and GGT) and liver metabolites (albumin, bilirubin, urea and creatinine), as well as plasma levels of IL-6, IL-8, TNF-α and TGF-β, were not affected by MSC transplantation. In our novel, large animal (pig) model of repeated biliary obstruction followed by partial hepatectomy, MSC transplantation promoted growth of liver tissue without any effect on liver function. This study underscores the importance of translating results between small and large animal models as well as the careful translation of results from animal model into human medicine.

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First Report on Ex Vivo Delivery of Paracrine Active Human Mesenchymal Stromal Cells to Liver Grafts During Machine Perfusion

Cited by 27 publications

References 4 publications

The Immunological Basis of Liver Allograft Rejection

The Immunological Basis of Liver Allograft Rejection

Mesenchymal Stromal Cells, a New Player in Reducing Complications From Liver Transplantation?

Mesenchymal Stromal Cell Therapy in Novel Porcine Model of Diffuse Liver Damage Induced by Repeated Biliary Obstruction

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