Bioartificial Livers Developed From Gene-Edited Pig Hepatocyte Organoids Improve Amino Acid and Lipid Profiles in the Plasma of Patients With Liver Failure

Abstract

Liver failure remains a life-threatening syndrome where the available therapeutic options are extremely limited beyond transplantation. This study addresses critical cell source and mechanistic challenges by developing a novel bioartificial liver (BAL) system. We utilized CRISPR/Cas9 technology to knockout the GGTA1 gene in primary porcine hepatocytes to reduce immunogenicity. These hepatocytes were co-cultured with R-spondin1-overexpressing human umbilical vein endothelial cells (R-HUVECs) to form functionally stable liver organoids. In ex vivo study using plasma from patients with acute-on-chronic liver failure (ACLF), the BAL system demonstrated superior detoxification, significantly reducing ammonia and bilirubin levels compared to traditional non-bioartificial liver (NAL) support. Multi-omics analyses revealed that BAL treatment actively restored metabolic homeostasis by promoting branched-chain amino acid (BCAA) metabolism and upregulating lysophosphatidylcholine (LPC) species associated with membrane repair and anti-inflammatory signaling. Significantly, this research demonstrates that unlike the passive physical filtration of NAL, BAL serves as an active biological regulator of systemic metabolism. These findings provide a robust theoretical and practical foundation for the clinical translation of BAL technology, offering a promising strategy to improve outcomes for liver failure patients by modulating systemic metabolism.

Keywords

bioartificial liver / gene editing / liver failure / liver organoids / metabolomics

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