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The limited replicative potential of primary hepatocytes (Hep) is a major hurdle for obtaining sufficient quantity and quality hepatocytes during cell therapy in patients with liver failure. Intrahepatic cholangiocyte organoids (ICOs) derived from intrahepatic bile ducts differentiate into both hepatocytes and cholangiocytes in vitro. Here, we studied in vivo effects of transplanting ICOs and Hep in chronic liver injury mice models. Well characterized primary mouse ICOs and Hep were mixed in decellularized liver (DCL) matrix hydrogels and injected into the subcapsular left lateral liver lobe of CCl4-induced liver injury models whereas mice given DCL alone were in the sham group. Two weeks post-transplantation, transplanted liver lobes were collected and studied by histology and RNA sequencing. Transplanted animals did not exhibit any tumors, mortality or morbidity. Mice livers transplanted with ICOs had increased cellular proliferation and vascularization as compared to Hep transplanted mice or sham. Collagen deposition in the liver was significantly reduced and serum albumin levels were significantly increased in transplanted groups compared to the sham group. Expression of genes associated with hepatocyte differentiation was highest in Hep transplanted livers among the three groups, but they were also upregulated in ICO transplanted livers compared to sham. Our study demonstrates that ICOs encapsulated in DCL hydrogels when transplanted in chronically injured mice livers engraft well and show hepatocyte differentiation and reduction of fibrosis, indicating that hydrogel transplanted cholangiocyte organoids may serve as an efficient cell source and therapy for renewal of hepatocytes, restoration of hepatocyte functions and resolution of liver injury. [ABSTRACT FROM AUTHOR]

Gut metabolites via the portal vein affect several liver functions, including regeneration. Here, we investigated gut microbiota-derived metabolites in portal and peripheral serum during liver regeneration. We developed rat models of 70% partial hepatectomy (PHx) with and without prior gut microbiota modulation by 3-wk antibiotic (Abx) treatment. Sham without Abx were used as controls and compared with sham with Abx. Liver regeneration at day 2 following PHx was assessed by expression of proliferating cell nuclear antigen (PCNA) protein in liver tissues and cyclin genes in primary hepatocytes. High-performance liquid chromatography-mass spectrometry-based portal and peripheral venous serum metabolomics were performed to identify differentially altered metabolites (DAMs). Compared with controls, rat livers at day 2 post-PHx showed significant upregulation in the average number of PCNA-positive cells, which positively correlated with the expression of cell cycle genes in hepatocytes. In Abx-treated PHx, we observed reduced PCNA-positivity and downregulation in gene expression of various cyclins in hepatocytes compared with PHx. We identified 224 DAMs between controls versus PHx and 189 DAMs between Abx-treated PHx versus PHx in portal serum. Many common DAMs showed opposite expression trends in PHx versus controls and then Abx + PHx versus PHx in portal serum, such as sphingosine-1-phosphate and deoxycholic acid. In vitro studies with deoxycholic acid demonstrated that it enhanced the viability and proliferation of primary hepatocytes and hepatocyte organoids. The study underscores the critical role of deoxycholic acid in portal blood in enhancing hepatocyte proliferation and, subsequently, liver regeneration. NEW & NOTEWORTHY: Based on metabolome analysis of portal and peripheral serum in 70% partial hepatectomy (PHx) models, we described previously unreported metabolic alterations related to liver regeneration. The study also identified substantial changes among portal and peripheral serum metabolites in both control and PHx rats. We identified the potential role of portal vein metabolites including sphingosine-1-phosphate and deoxycholic acid in promoting hepatocyte proliferation and, hence, liver regeneration following PHx. [ABSTRACT FROM AUTHOR]

Correction for 'In vivo transplantation of intrahepatic cholangiocyte organoids with decellularized liver-derived hydrogels supports hepatic cellular proliferation and differentiation in chronic liver injury' by Impreet Kaur et al., J. Mater. Chem. B, 2025, 13, 918–928, https://doi.org/10.1039/D4TB01503G. [ABSTRACT FROM AUTHOR]