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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: Bile duct (BD) structure is crucial for bile secretion to maintain liver homeostasis. Although several human induced pluripotent stem cell (hiPSC)-derived liver organoids have been generated, no study recapitulates the development of BD tubules. Here, we focus on an environmental cue to form tubular BDs, specifically the interaction between liver progenitors with the portal vein (PV). We co-culture hiPSC-liver progenitors with PV-like hiPSC-blood vessel (hiPSC-BV) which consists of immature hiPSC-smooth muscle cells (SMC) with a similar character to fetal PV-SMC. After two weeks, liver progenitors within hiPSC-BV-integrated liver organoid (BVLO) differentiate into the cholangiocyte-lineage and establish tubular structures with epithelial characteristics including intercellular junctions, microvilli on the apical membrane, and secretory functions. Liver surface transplanted BVLO showed further BD maturation and connection to the host BD. Taken together, our study developed a novel 3D co-culture methodo establish functional human tubular BDs by recapitulating PV-BD interaction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270413 | GEO | 2024/07/16

REPOSITORIES: GEO

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

Project description:Bile duct (BD) structure is crucial for bile secretion to maintain liver homeostasis. Although several human induced pluripotent stem cell (hiPSC)-derived liver organoids have been generated, no study recapitulates the development of BD tubules. Here, we focus on an environmental cue to form tubular BDs, specifically the interaction between liver progenitors with the portal vein (PV). We co-culture hiPSC-liver progenitors with PV-like hiPSC-blood vessel (hiPSC-BV) which consists of immature hiPSC-smooth muscle cells (SMC) with a similar character to fetal PV-SMC. After two weeks, liver progenitors within hiPSC-BV-integrated liver organoid (BVLO) differentiate into the cholangiocyte-lineage and establish tubular structures with epithelial characteristics including intercellular junctions, microvilli on the apical membrane, and secretory functions. Liver surface transplanted BVLO showed further BD maturation and connection to the host BD. Taken together, our study developed a novel 3D co-culture method o establish functional human tubular BDs by recapitulating PV-BD interaction.

2024-07-16 | GSE198888 | GEO

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

Project description: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.

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Project description:Persistent bronchial dysplasia (BD) is associated with increased risk of developing invasive squamous cell carcinoma (SCC) of the lung. We hypothesized that differences in gene expression profiles between persistent and regressive BD would identify cellular processes that underlie progression to SCC. RNA expression arrays (Affymetrix Hu 1.0) comparing baseline biopsies from 32 bronchial sites that persisted/progressed to 31 regressive sites showed 395 differentially expressed genes (ANOVA, FDR</=0.05). Thirty-one pathways showed statistically significant evidence of altered activity between the two groups. Multiple pathways were associated with cell cycle control/proliferation, inflammation, or epithelial differentiation/cell-cell adhesion. Polo-like kinase 1 (PLK1) was associated with multiple cell cycle pathways. Cultured persistent BD cells showed increased PLK1 expression, and following treatment with PLK1 inhibitor, showed induction of apoptosis, G2/M phase arrest and decreased proliferation compared to untreated cells. These effects were not seen in normal or regressive BD cultures. Inflammatory pathway activity was decreased in persistent BD and the presence of an inflammatory infiltrate was more common in regressive BD. Regressive BDs were also associated with trends toward overall increases in macrophages and T-lymphocytes and altered polarization of these inflammatory cell subsets. Increased desmoglein 3 and plakoglobin expression was associated with higher grade and persistence of BD. The results identify alterations in cell cycle control, inflammatory activity, and epithelial differentiation/cell-cell adhesion in the persistent subset of BDs that are associated with high risk for progression to invasive SCC. These pathways may provide strong markers of risk and effective targets for lung cancer prevention.

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Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking

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Single-cell RNA sequencing data from hiPSC disease modeling of Loeys-Dietz Syndrome (LDS)

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Periportal macrophages protect against commensal-driven liver inflammation [spatial transcriptomics]

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Periportal macrophages protect against commensal-driven liver inflammation

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2024-03-20 | GSE261560 | GEO

TCF7L2 lncRNA: A Link between Bipolar Disorder and Body Mass Index through Glucocorticoid Signaling [RNA-Seq]

Project description:Bipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI) which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells which highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas which are involved in metabolism. In astrocytes, knock-down of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knock-down with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD-risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.

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