Human Embryonic Stem Cell-derived Expandable Hepatic Organoids Enable Pathophysiological Model of Alcoholic Liver Injury
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA528629 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8769770_1.fastq.gz | Fastqsanger.gz | |||
| SRR8769770_2.fastq.gz | Fastqsanger.gz | |||
| SRR8769780_1.fastq.gz | Fastqsanger.gz | |||
| SRR8769780_2.fastq.gz | Fastqsanger.gz | |||
| SRR8769771_1.fastq.gz | Fastqsanger.gz |
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Project description:We report the generation of human pluripotent-stem-cell-derived (hPSC), expandable hepatic organoids (hEHOs) using a newly established method that consists of subjecting hPSCs to a sequence of distinct wholly defined (serum-free, feeder free) media lineage restricting the cells to become determined hepatic stem cells followed by a process of shifting the cells from monolayer (2D) to organoid (3D ) cultures. The hEHOs stably keep phenotypic features of a bi-potent hepatic lineage that can differentiate into functional hepatocytes or cholangiocytes. The hEHOs can expand for over 20 passages enabling industrial scaling to amounts requisite for industry or clinical programs. The cells from culture are able to engraft rapidly into injured liver parenchyma of FRG mice following transplantation and to differentiate in vivo into mature hepatocytes. If implanted into the epididymis fat pads of immune-deficiency mice, they do not generate non-hepatic lineages nor teratomas. We further developed a derivative model by incorporating human fetal liver mesenchymal cells (hFLMCs) into the hEHOs, referred as hFLMC/hEHO, and used the organoids to model alcohol liver disease-associated pathophysiologic changes, such as oxidative stress generation, steatosis, inflammatory mediators release and fibrosis, following treatment with alcohol. Our work demonstrates that the hFLMC/hEHO provide a novel ex vivo pathophysiological model for studying alcohol liver disease as well as many other non-genetic liver diseases.
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Project description:We report the generation of human ESC-derived, expandable hepatic organoids (hEHOs) using our newly established method with wholly defined (serum-free, feeder free) media. The hEHOs stably maintain phenotypic features of bipotential liver stem/progenitor cells that can differentiate into functional hepatocytes or cholangiocytes. The hEHOs can expand for 20 passages enabling large scale expansion to cell numbers requisite for industry or clinical programs. The cells from hEHOs display remarkable repopulation capacity in injured livers of FRG mice following transplantation, and they differentiate in vivo into mature hepatocytes. If implanted into the epididymal fat pads of immune-deficient mice, they do not generate non-hepatic lineages and have no tendency to form teratomas. We further develop a derivative model by incorporating human fetal liver mesenchymal cells (hFLMCs) into the hEHOs, referred to as hFLMC/hEHO, which can model alcoholic liver disease-associated pathophysiologic changes, including oxidative stress generation, steatosis, inflammatory mediators release and fibrosis, under ethanol treatment. Our work demonstrates that the hEHOs have considerable potential to be a novel, ex vivo pathophysiological model for studying alcoholic liver disease as well as a promising cellular source for treating human liver diseases.
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Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.
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Project description:The following is an excerpt from the abstract of Miller et al. In this study, we find that two transcription factors, MYCN and SOX17, enable the indefinite propagation of human endothelial arterial precursors in vitro (“expandable arterial endothelial precursors,” eAEPs). Independent eAEP lines differ in their proclivity to undergo an endothelial-to-mesenchymal transition (EndoMT), a hallmark event in a broad array of vascular diseases and disorders. Some lines spontaneously become mesenchymal over time in culture, an effect exacerbated by inhibition of the fibroblast growth factor (FGF) receptor, while others do not readily convert. These distinctions were exploited to identify genes that correlate with resistance to an EndoMT and to elucidate transcriptional changes that underpin the transition. We believe the eAEPs may be useful not only as tractable tools for biological or pathological studies, but also as platforms for drug discovery.
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