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Generation of 3D tubular bile duct within human iPSC-derived liver organoid by incorporating human iPSC-derived blood vessel [scRNA-seq]

ABSTRACT: The tubular structure of the intrahepatic bile duct (BD) is crucial for its physiological functions including bile excretion. Although several human induced pluripotent stem cell (hiPSC)-derived liver organoids were generated, no prior study could emulate the development of BD tubules. Here we focus on the environmental cue to initiate BD development, specifically the interaction between liver progenitors and the portal vein (PV). We co-cultured hiPSC-liver progenitors with hiPSC-blood vessels (hiPSC-BV) consisting of immature hiPSC-smooth muscle cells (SMC) expressing JAG1, a key factor for cholangiocyte induction. After three weeks, liver progenitors within hiPSC-BV-integrated liver organoids (BVLO) differentiate into cholangiocyte lineage and establish tubular structures with epithelial characteristics, including intercellular junctions, microvilli on the apical membrane, and secretory functions. Furthermore, liver surface transplanted-BVLO demonstrated BD graft-host connection and suggested therapeutical potential. Overall, we developed a novel 3D co-culture method to establish functional human tubular BDs by emulating PV-BD interaction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240019 | GEO | 2024/07/16

REPOSITORIES: GEO

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Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases. Total RNA isolated using TRI Reagent (Sigma, St. Louis, MO) was purified with an RNeasy mini kit (Qiagen, Valencia, CA). Twenty micrograms cRNA was hybridized to a mouse GeneChip (U74Av2, Affymetrix, Santa Clara, CA) at the Siteman Cancer Center GeneChip facility as described by the manufacturer. Analyses used one mouse per chip. Gene expression changes were analyzed using Affymetrix MicroArray Suite 4.0 and GeneChip 3.1 Expression Analysis and Statistical Algorithms (Affymetrix). The complete methodology and full data sets for all 6 analyzed chips are available at http://bioinformatics.wustl.edu.beckerproxy.wustl.edu This study compares the injury and repair processed in wild-type mice after BDL.

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Generation of 3D tubular bile duct within human iPSC-derived liver organoid by incorporating human iPSC-derived blood vessel [scRNA-seq]

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