Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA260672 | ENA |
REPOSITORIES: ENA
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Project description:Various adaptive cellular stress response pathways are critical in the pathophysiology of liver disease and drug-induced liver injury. Human-induced pluripotent stem cell (hiPSC)-derived hepatocyte-like cells (HLCs) provide a promising tool to study cellular stress response pathways, but in this context there is limited insight on how HLCs compare to primary human hepatocytes (PHH). Here, we systematically compared the activation of four different stress pathways in PHH, HepG2 liver cancer cells, hiPSCs and different stages within the differentiation towards HLCs (definitive endoderm, hepatoblast, immature hepatocytes and HLCs). We exposed all different cell types in a concentration response to four different compounds that specifically activate the oxidative stress response (diethyl-maleate), unfolded protein response (tunicamycin), DNA damage response (cisplatin) and inflammatory signalling (TNF). We used targeted RNA-sequencing to map concentration response transcriptional similarities and differences using bench-mark concentration modelling for the various stress responses in the different test systems. We observed that HLCs are more sensitive to oxidative stress than PHH showing activation at ten-fold lower concentrations and induce a strong anti-oxidant response. Although similar UPR gene sets were activated in HLCs compared to PHH, PHH were about ten times more sensitive. Furthermore, HLCs were highly sensitive to inflammation conditions similar to HepG2 cells and in sharp contrast to hiPSC, which showed hardly any response. On the contrary, hiPSC and HepG2 were highly sensitive to DNA damage signalling while HLCs resisted a strong p53 DNA damage response upon exposure. Overall, the data indicate that despite limitation in full hepatocyte maturation, HLCs did gain specific adaptive cellular stress response networks that mimic those of PHHs.
2021-02-18 | GSE155771 | GEO
Project description:Interindividual differences in hepatic metabolism, which are mainly due to genetic polymorphism in its gene, have a large influence on individual drug efficacy and adverse reaction. Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells have the potential to predict interindividual differences in drug metabolism capacity and drug response. However, it remains uncertain whether human iPSC-derived HLCs can reproduce the interindividual difference in hepatic metabolism and drug response. We found that cytochrome P450 (CYP) metabolism capacity and drug responsiveness of the primary human hepatocytes (PHH)-iPSHLCs were highly correlated with those of PHHs, suggesting that the PHH-iPS-HLCs retained donor-specific CYP metabolism capacity and drug responsiveness. We also demonstrated that the interindividual differences, which are due to the diversity of individual SNPs in the CYP gene, could also be reproduced in PHH-iPS-HLCs. We succeeded in establishing, to our knowledge, the first PHH-iPS-HLC panel that reflects the interindividual differences of hepatic drugmetabolizing capacity and drug responsiveness.
2014-11-12 | GSE61287 | GEO
Project description:Induced pluripotent stem cells (iPSCs) are similar to embryonic stem cells and can be generated from somatic cells. We have generated episomal plasmid-based and integration-free iPSCs (E-iPSCs) from human fetal foreskin fibroblast cells (HFF1). E-iPSCs were fully characterized and their transcriptomes are more similar to that of hESCs (R2 = 0.9363) in comparison to viral-derived HFF1-iPSCs (R2 = 0.8176). We used an E-iPSC-line to model hepatogenesis in vitro. The differentiation of iPSCs into hepatocyte-like cells (HLCs) is a three-step process, from the undifferentiated E-iPSC to definitive endoderm (DE), hepatic endoderm (HE) and ultimately HLCs. The HLCs were characterized biochemically, i.e. glycogen storage, ICG uptake and release, UREA and bile acid production, as well as CYP3A4 activity. Ultra-structure analysis by electron microscopy revealed the presence of lipid and glycogen storage, tight junctions and bile canaliculi- all typical features of hepatocytes. Furthermore, the transcriptome of undifferentiated E-iPSC, DE, HE and HLCs were compared to that of fetal liver and primary human hepatocytes (PHH). K-means clustering identified 100 clusters which include developmental stage-specific groups of genes, e.g. OCT4 expression at the undifferentiated stage, SOX17 marking the DE stage, DLK and HNF6 the HE stage, HNF4a and Albumin is specific to HLCs, fetal liver and adult liver (PHH) stage. The lack of viral DNA integrations in these E-iPSCs endow them superior to viral-derived iPSCs for (i) modeling gene regulatory networks associated with hepatogenesis and gastrulation in general, (ii) toxicology studies and (iii) drug screening platforms.
2017-09-06 | GSE66282 | GEO
Project description:ChIP-sequencing was performed to explore the difference between the epigenetic profiles of hepatocyte-like cells (HLCs) generated in vitro and primary human hepatocytes (PHHs). HLCs were differentiated from hIPSCs and hESCs for 30 days, as previously reported (Hannan et al, 2013). PHHs were purchased from Biopredic. Chromatin was immunoprecipitated with antibodies against H3K27ac, H3K4me1, H3K27me3 and H3K4me3. Library preparation and sequencing were performed by the Wellcome Trust Sanger Institute DNA Sequencing Facility (Hinxton, UK). Sequencing was performed on an Illumina HiSeq v4 instrument to obtain paired-end reads with 75bp length.
2022-08-11 | E-MTAB-10637 | biostudies-arrayexpress
Project description:The purpose of this experiment was to compared the transcriptome of hepatocyte-like cells (HLCs) generated in vitro and adult primary human hepatocytes (PHHs). HLCs were differentiated from either hESCs or hIPSCs using previously established protocols (Hannah et al 2013; Segeritz et al 2018). Undifferentiated hIPSCs were used as control to confirm differentiation status. PHHs were commercially sourced as well as freshly isolated from donors.
2022-08-11 | E-MTAB-10634 | biostudies-arrayexpress
Project description:Background: Hepatocyte-like cells (HLCs) differentiated from induced pluripotent stem cells (iPSCs) have emerged as a promising cell culture model to study metabolism, biotransformation, viral infections and genetic liver diseases. However the derivation of iPSCs is restricted by ethical and procedural constraints. Furthermore, incomplete HLC differentiation remains a major challenge. iPSC may carry-on a tissue of origin dependent expression memory influencing iPSC differentiation into different cell types. If liver derived iPSCs (Li-iPSCs) maintain a liver specific gene expression profile is not known. It is also not known, if Li-iPSCs would allow the generation of more fully differentiated HLCs.Methods: Primary liver cells (PLCs) were expanded from liver needle biopsies and reprogrammed into Li-iPSCs using a non-integrative Sendai virus-based system. Li-iPSCs were differentiated into HLCs using established differentiation protocols. The HLC phenotype was characterized at the protein, functional and transcriptional level. RNA sequencing data were generated from the originating liver biopsies, the Li-iPSCs, fibroblast derived iPSCs, and differentiated HLCs, and used to characterize and compare their transcriptome profiles.Results: PLCs were obtained from small pieces of liver biopsies and could be reprogrammed into Li-iPSCs. Li-iPSCs indeed retain a liver specific transcriptional footprint. Li-iPSCs can be propagated to provide an unlimited supply of cells for differentiation into Li-HLCs. Similar to HLCs derived from fibroblasts, Li-HLCs could not be fully differentiated into hepatocytes. Relative to the originating liver, Li-HLCs showed lower expression of liver specific transcription factors and increased expression of genes involved in the differentiation of other tissues.Conclusions: PLCs and Li-iPSCs obtained from small pieces of human needle liver biopsies constitute a novel unlimited source for the production of HLCs. Despite the preservation of a liver specific gene expression footprint in Li-iPSCs, the generation of fully differentiated hepatocytes cannot be achieved with the current differentiation protocols.
| EGAS00001002676 | EGA
Project description:Gene expression profiles for ~20,000 genes using Illumina Homo sapiensRef-8 v2
2010-03-25 | GSE21045 | GEO
Project description:Global gene-expression profiles analysis of iPSCs
| PRJNA143863 | ENA
Project description:Gene expression profiling of immortalized human mesenchymal stem cells with hTERT/E6/E7 transfected MSCs. hTERT may change gene expression in MSCs. Goal was to determine the gene expressions of immortalized MSCs.
2010-09-25 | GSE24338 | GEO
Project description:Two independent protocols for deriving HLCs from hESCs and iPSCs were adopted and further characterization included immunocytochemistry, real-time RT-PCR, and in vitro functional assays. Comparative microarray-based gene expression profiling was conducted on these cells and compared to the transcriptomes of human fetal liver and adult liver progenitors. HLCs derived from hESCs and hiPSCs showed significant functional similarities, similar expression of genes important for liver physiology and common pathways. However, specific differences between the two cell types could be observed. Total RNA obtained from undifferentiated hESCs, iPSCs, HLCs (hepatocyte-like cells)-derived from hESCs and iPSCs, fetal forskin fibroblasts and fetal liver.
2011-01-20 | E-GEOD-25744 | biostudies-arrayexpress