In a study published in Cell Stem Cell, researchers led by Prof. HUI Lijian from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences reported that the efficacy and safety of encapsulated proliferating human hepatocyte organoids in treating liver failure, guaranteeing the ongoing IIT (investigator initiated trial) study.
Acute liver failure is a devastating disease with a high mortality. Until now, liver transplantation remains the only effective treatment for liver failure. Due to the shortage of liver organs, alginate-encapsulated primary human hepatocytes (PHHs) transplantation is a promising strategy to treat liver failure, e.g. in the treatment of acute phase of liver failure or bridging for liver transplantation. However, its clinical application was impeded by the lack of primary human hepatocytes and the difficulty to control their quality.
Recently, the researchers dedifferentiated PHHs into bi-phenotypic status without genetic manipulation (proliferating human hepatocytes, ProliHHs). Showing features of both hepatocytes and progenitors, ProliHH could be expanded for at least 10,000-fold. Importantly, ProliHH could be re-differentiated into a mature status close to PHH in a three-dimensional organoid system, making them the prospective cell resource in hepatocyte-based therapy.
In this study, quality-controlled ProliHHs were produced in mass and engineered as liver organoids to improve their maturity. Encapsulated liver organoids (eLO) maintained long-term viability and function during the in vitro culture. Next, eLO were intraperitoneally transplanted to treat liver failure animals. Notably, Encapsulation by alginate, due to its outstanding biocompatibility, generated an immune-protective and semipermeable barrier for the encapsulated LO, allowing the supply of nutrients and oxygen and the export of secreted therapeutic proteins, and enabled the long-term retention and the retrieval of eLO. eLO treatment increased the survival of mice with post-hepatectomy liver failure (PHLF) and ameliorated hyperammonemia and hypoglycemia by providing liver functions. Additionally, eLO treatment protected gut from PHLF-augmented permeability and normalized the increased serum endotoxin and inflammatory response, which facilitated liver regeneration. The therapeutic effect of eLO was additionally proved in acetaminophen-induced liver failure. Furthermore, the researchers performed assessments of toxicity and biodistribution, demonstrating that eLO had no adverse effects on animals and remained non-tumorigenic.
In summary, these research findings demonstrate the efficacy and safety of eLO in the treatment of liver failure and propose the perspective about intestinal endotoxemia in PHLF-induced liver regeneration and the potential feasibility to initiate the further clinical study of eLO treatment in liver failure in the future.
Contact: huilab@sibcb.ac.cn
Reference：https://www.sciencedirect.com/science/article/pii/S1934590924000481
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