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Safety of stem cell-derived encapsulated liver tissue to treat liver failure: Immune-isolation and absence of foreign body reaction or tumor formation upon transplantation without immunosuppression

      Acute liver failure (ALF) is a severe condition resulting in <50% survival if the patient is not transplanted. The standard of care for liver failure is liver transplantation, which, besides entailing a still significant short-term mortality and morbidity risk, requires lifelong immunosuppression and is often complicated by severe long-term hepatic and extra-hepatic sequelae. Because of organ shortage, and since no effective blood purification system exist to replace liver functions, death waiting for transplant is far too common. We developed an innovative stem cell-based product capable of restoring liver functions upon implantation, without the need of immunosuppression and with no risk of tumor formation. Starting from a single clinical-grade induced pluripotent stem cell population, we are able to generate complex 3D organoids performing the functions of the human liver in a dish. We optimized all protocols to ease future scale-up and GMP implementation. We developed a non-degradable, semi-solid, polyethylene glycol-based biomaterial to encapsulate these liver organoids, promoting their maturation and minimizing inflammatory reaction upon implantation. The obtained Encapsulated Liver Tissue, which contains hundreds organoids into a single gel, is capable of performing synthetic and metabolic functions specific to the human liver more effectively than freshly-isolated primary hepatocytes. Such functions are maintained long term (>8 weeks) and are not affected by cryopreservation. Data from mixed lymphocyte reaction assay carried out on activated dendritic cells and liver organoids, with and without encapsulation, show that the biomaterial isolates embedded cells and organoids from allogeneic T cells completely, thus eliminating the risk of rejection and the need for immunosuppression. We also showed in immunosuppressed NSG mice that encapsulation prevents embedded highly tumorigenic cells from spreading throughout the recipient body, eliminating the risk of tumor formation. Our preliminary short-term in vivodata show that the ELT restores liver functions and prevent death and major morbidity in immunocompetent FAH-/- mice with ALF without immunosuppression, without any sign of rejection, foreign body reaction or tumor formation. Overall the ELT has the potential of being developed into a good-for-all, off-the-shelf, implantable device to replace liver functions in patients with liver failure without the need of immunosuppression.
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