2025-10-02 大阪大学
Web要約 の発言:
図1: UTOpiAシステムの概略と治療効果
A. UTOpiAの構成要素と概念図 B.慢性肝不全急性憎悪に対する治療効果
<関連情報>
- https://www.med.osaka-u.ac.jp/activities/results/2025year/takebe2025-10-02
- https://www.journal-of-hepatology.eu/article/S0168-8278(25)02477-8/fulltext
HLA除去肝オルガノイドと顆粒球単球アフェレーシスを組み合わせた全血体外システムを用いたACLFおよびALFの逆転 Reversal of ACLF and ALF using whole blood extracorporeal system combining HLA-depleted liver organoids with granulocyte-monocyte apheresis
Hitomi Yamaguchi ∙ Yosuke Yoneyama ∙ Kentaro Ichimura ∙ … ∙ Robert P. Myers ∙ G. Mani Subramanian ∙ Takanori Takebe
Journal of Hepatology Published:October 2, 2025
DOI:https://doi.org/10.1016/j.jhep.2025.08.038
Highlights
- HLA-A, HLA-B, and CIITA triple knockout iPSCs can generate iHLCs with metabolic and detoxification functions.
- UTOpiA combines iHLCs and GMA to rescue preclinical models of ACLF and ALF.
- UTOpiA suppresses neutrophil infiltration and systemic inflammation.
- AFP secretion from iHLCs promotes liver regeneration in ACLF rats.
- The tandem GMA-iHLC circuit enables whole blood bioartificial liver therapy.
Abstract
Background & Aims
Acute-on-chronic liver failure (ACLF) is characterized by catastrophic loss of liver function in patients with advanced chronic liver disease, with 28-day mortality rates reaching up to 80%. Despite advances in intensive care, the high mortality primarily stems from the absence of a therapeutic modality that simultaneously addresses both the profound systemic inflammatory response and severe hepatic synthetic dysfunction.
Methods
We designed an integrated extracorporeal circuit, termed the UTOpiA system, which combines granulocyte and monocyte apheresis (GMA) with human induced pluripotent stem cell-derived hepatocyte-like cell (iHLC) organoids engineered with HLA-A, HLA-B, and CIITA triple knockout. The efficacy of UTOpiA was tested after direct whole blood exposure through venous flow in rat models of ACLF and acute liver failure (ALF).
Results
UTOpiA treatment significantly improved survival in both ACLF and ALF rat models, outperforming GMA or iHLC monotherapy and HepG2 cell-based devices. Improved survival was associated with reduced coma severity, improved liver biochemistry, and reduced hyperammonaemia, hyperbilirubinemia, and systemic inflammation. Transcriptomic and histological analyses revealed restoration of hepatic metabolic gene expression and hepatocyte regeneration. Mechanistically, iHLC-secreted α-fetoprotein suppressed hepatocyte cell cycle arrest via p21 downregulation and enhanced regeneration, while UTOpiA restored HNF4α activity and dampened pro-inflammatory cytokines, including IL-6 and TNF-α.
Conclusions
The tandem UTOpiA circuit confers a significant survival benefit in preclinical rodent models of ACLF and ALF by providing anti-inflammatory, synthetic, and metabolic support. Elucidating the regenerative signals that promote recovery of the injured liver may further expand the potential of this whole blood extracorporeal system as a novel, off-the-shelf liver support therapy.
Impact and implications
Restoring hepatic metabolism while controlling inflammation in acutely decompensated cirrhosis remains a major unmet clinical need. By combining HLA-modified human induced pluripotent stem cell–derived liver organoids with granulocyte and monocyte apheresis, we developed a bioartificial liver system that manages inflammation, restores liver function, and promotes regeneration in two rat models of severe liver failure. This therapy could offer an off-the-shelf treatment option for patients with life-threatening liver failure.
