Extracorporeal liver support system utilizing low-immunogenicity liver organoids developed by Institute of Science Tokyo and the University of Osaka

Dr. Hitomi Yamaguchi of the Graduate School of Medical and Dental Sciences at the Institute of Science Tokyo, along with Lecturer Yosuke Yoneyama and Professor Takanori Takebe of the Graduate School of Medicine at the University of Osaka, announced on October 3 that they have developed an extracorporeal liver support therapy called "UTOpiA" that incorporates iPSC-derived liver organoids. When the system was used in rat models of acute-on-chronic liver failure (ACLF) and acute liver failure, they succeeded in significantly improving survival rates. Reduction in hepatocyte injury and recovery of liver regenerative capacity were also confirmed. They aim to conduct clinical research within the next 2-3 years and achieve commercialization in 5-7 years. Their findings were published in the October 3 issue of Journal of Hepatology.

ACLF is a condition where people with chronic liver disease such as cirrhosis experience sudden deterioration of liver function triggered by events such as infection or heavy alcohol consumption, resulting in multiple organ failure. For severe cases, the 30-day survival rate is as low as approximately 20%, and no established treatment exists. Currently, the only curative therapy is liver transplantation, but there is a shortage of donors.

The research group had previously succeeded in creating functional multi-layered liver organoids - i.e., human induced pluripotent stem (iPS) cell-derived hepatocyte-like cells (iHLCs).

In these developments, the research group devised the UTOpiA system, which combines a GMA column - that is already in practical use for suppressing inflammation in inflammatory diseases and is intended to remove granulocytes and monocytes from the blood - with metabolic function supplementation by iHLCs.

To treat ACLF, it was necessary to suppress strong systemic inflammation, supplement the metabolic functions reduced by chronic liver disease, and promote regeneration that had declined due to liver disease.

The group received low-immunogenicity (HLA-deficient) iPS cells from the CiRA Foundation and created iHLCs. They aimed to prevent immune rejection and enable application to a wide range of patients.

The iHLCs created after approximately 20 days of culture showed liver functions such as protein synthesis and ammonia/bilirubin metabolism. Furthermore, to enhance safety, iHLCs were embedded in alginate (gel) and encapsulated. The researchers developed the UTOpiA system by filling columns (iHLC columns) with capsules containing several hundred iHLCs per capsule and connecting them in series behind the GMA column. The iHLC columns contain approximately 300 cells.

In the experiments, using a dialysis-like procedure, survival rates were compared among untreated, empty column, single column only, and UTOpiA system groups in an ACLF rat model where all untreated animals died within 48 hours.

As a result, the 48-hour survival rate with the UTOpiA system was the highest at approximately 90%.

The group also confirmed that treatment with the system reduced blood concentrations of ammonia and bilirubin and decreased liver tissue injury scores after 72 hours. Furthermore, they confirmed that cell proliferation in the ACLF native liver increased, the proliferation inhibitor p21 decreased, and regeneration was promoted. They also confirmed that this high regeneration-promoting effect was due to iHLCs being immature cells. They are currently preparing for trials in large animals.

Journal Information
Publication: Journal of Hepatology
Title: Reversal of ACLF and ALF using whole blood extracorporeal system combining HLA-depleted liver organoids with granulocyte-monocyte apheresis
DOI: 10.1016/j.jhep.2025.08.038