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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Global gene expression profiles of mouse ESCs, disease-specific iPSCs, and gene-corrected iPSCs

ABSTRACT: The use of patient-derived induced pluripotent stem (iPS) cells as treatment for genetic diseases entails genetic repair or transfer of genetic information as a prerequisite. We have chosen the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase deficiency; FAH(-/-) mice) as a paradigm for hereditary metabolic liver disorders and evaluated fibroblast-derived FAH(-/-)-iPS cell lines as targets for gene correction. By aggregating FAH(-/-)-iPS cells with tetraploid embryos, we obtained FAH-/--iPS cellâderived mice, which exhibited the phenotype of the founding FAH(-/-)-mice. We then rescued the diseased phenotype by lentiviral transduction of FAH-cDNA and performed embryo aggregation with these gene-corrected FAHgc-iPS cells to obtain viable healthy mice. Our results demonstrate that iPS cell technology is a valid approach to establish mouse disease models directly from somatic cells bearing genetic defects. Furthermore, established iPS cell lines can be genetically manipulated without loss of pluripotency for treatment of genetic diseases. 6 samples: 1 MEF, 1ESC, 4 iPSCs

ORGANISM(S): Mus musculus

SUBMITTER: Boris Greber

PROVIDER: E-GEOD-21343 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Global gene expression profiles of mouse ESCs, disease-specific iPSCs, and gene-corrected iPSCs

Project description:The use of patient-derived induced pluripotent stem (iPS) cells as treatment for genetic diseases entails genetic repair or transfer of genetic information as a prerequisite. We have chosen the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase deficiency; FAH(-/-) mice) as a paradigm for hereditary metabolic liver disorders and evaluated fibroblast-derived FAH(-/-)-iPS cell lines as targets for gene correction. By aggregating FAH(-/-)-iPS cells with tetraploid embryos, we obtained FAH-/--iPS cell–derived mice, which exhibited the phenotype of the founding FAH(-/-)-mice. We then rescued the diseased phenotype by lentiviral transduction of FAH-cDNA and performed embryo aggregation with these gene-corrected FAHgc-iPS cells to obtain viable healthy mice. Our results demonstrate that iPS cell technology is a valid approach to establish mouse disease models directly from somatic cells bearing genetic defects. Furthermore, established iPS cell lines can be genetically manipulated without loss of pluripotency for treatment of genetic diseases.

2010-04-16 | GSE21343 | GEO

Single cell transcriptomics of hepatostellate organoids derived from DKC1 A353V mutant and DKC1 A353V corrected iPSCs

Project description:We model liver phenotypes associated with telomere dysfunction using DC patient-derived iPS cells and isogenic controls with CRISPR/Cas9-mediated homology-directed repair correction of the disease-causing DKC1 mutation. Differentiation of these cells into hepatocyte-like cells or hepatic stellate cells indicates that the parenchymal hepatocytes are primarily affected by telomere dysfunction. We develop an admixed hepatostellate organoid culture model which further reveals that mutant hepatocytes exert dominant effects on hepatic stellate cells regardless of stellate cell genotype. Hepatostellate organoids containing DKC1-mutant hepatocytes exhibit hyperplasia in both the hepatocyte compartment and, remarkably, in stellate cells. Moreover, mutant hepatocytes can induce hallmarks of stellate cell activation independently of stellate cell genotype. Interestingly, mutant hepatostellate organoids also contain off-target PLVAP+ endothelial cells reminiscent of scar-associated endothelium observed in non-DC cirrhosis patients.

2022-02-28 | GSE188987 | GEO

Aneuploidy as a mechanism for stress-induced liver adaptation

Project description:Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question whether this unusual somatic genetic variation evolved as an adaptive mechanism to hepatic injury. According to this model, hepatotoxic insults would select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to the injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in homogentisic acid dioxygenase (Hgd), located on chromosome 16. Loss of this allele can protect from fumarylacetoacetate hydrolase (Fah) deficiency. When adult Hgd+/- Fah-/- mice were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury. The frequency of chromosome 16-specific aneuploidy was ~50%. This result provides proof-of-principle that the selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans is under investigation. 8 mouse hepatocyte samples were analyzed. Genomic DNA samples were derived from wild type mice (2), Hgd-/- Fah-/- mice off NTBC (2) and Hgd+/- Fah-/- off NTBC (4). Samples were compared to sex-mismatched reference genomic DNA isolated from wild type mouse splenocytes.

2012-07-16 | E-GEOD-38963 | biostudies-arrayexpress

Finger-prick iPSCs Facilitate the Development of Stem cell banking

Project description:Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients can be a good model for studying human diseases and for future therapeutic regenerative medicine. Current initiatives to establish iPSC banking face challenges in recruiting large numbers of donors with diverse diseased, genetic and phenotypic representations. Here, we describe the derivation of transgene-free iPSCs from human finger-prick blood. Fingerprick samples collection can be performed “DIY (Do-it-yourself)” by donors and sent to the iPSC facility for reprogramming. We show that single drop volumes of finger-prick samples are sufficient for performing cellular reprogramming, DNA sequencing and blood serotyping in parallel. Our novel strategy will facilitate the development of large scale iPSC banking world-wide. Total RNA from PBMC, hES cells, or iPS cells from PBMC was labeled with biotin. Samples were hybridized to HumanHT-12v4 Beadchip (Illumina) according to manufacturer’s protocol.

2014-03-28 | E-GEOD-53485 | biostudies-arrayexpress

Gene expression profiles in PHH-iPSCs, PHH-HLCs, PHHs, and HepG2

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

Transcription profiling of mouse wild type, Fah and Fah, p21 ON and OFF NTBC animals

Project description:Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Experiment Overall Design: Livers from adult wildtype, Fah or Fah, p21 knockout mice were analyzed either after continuous treatment (ON) with NTBC or after NTBC withdrawal for 14 days (OFF).

2008-06-11 | E-GEOD-11098 | biostudies-arrayexpress

Affymetrix CytoScan HD array data of iPSCs and iPSC-derived-NSPCs

Project description:Cytoscan HD analysis on DNA samples from iPSCs, iPS-derived NSPCs

2016-09-14 | GSE77995 | GEO

Expression data from SCA3 and genetically corrected iPSCs

Project description:The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3; also called Machado-Joseph disease, MJD) is a trinucleotide repeat disorder caused by expansion of CAG repeats which encoding an abnormal long polyglutamine (polyQ) tract in ataxin-3 of the ATXN3 gene. Even now the pathogenic mechanism has remained elusive and no cure method is currently available. In this study, we first applied CRISPR/Cas9-mediated approach using homologous recombination to achieve one-step genetic correction in SCA3-specific induced pluripotent stem cells (iPSCs) by adjusting pathological 80 CAG repeats to normal 13 CAG repeats, without detectable off-target based on whole exon sequencing or polyacrylamide gel electrophoresis (PAGE). The correction normalized SCA3 pathogenic signal pathways (like transcription, apoptosis, and ubiquitin-dependent protein catabolic process) and reversed disease-associated phenotypes. Our strategy provides deep insights into pathogenic mechanism of SCA3 disease and suggests potential therapeutic applications of trinucleotide repeat disorders.

2020-01-17 | GSE93713 | GEO

Isogenic pairs of MPS VI gene corrected iPSC and Chondrogenic cells

Project description:To investigate the effect of MPS VI on gene expression in chondrogenic cells, we gene corrected four patient derived hiPSC using a ARSB knock-in into the AAVS1 locus. We differentiated cells into chondrogenic cells using a 14 day protocol, we proformed gene expression profiling analysis using data obtained from RNA-seq at iPS stage in monoplo and differentiated cells in triplo.

2022-12-28 | GSE218101 | GEO

Transcriptional analysis of iPSCs during cellular reprogramming using RNA FACS

Project description:Mouse induced pluripotent stem cells (iPSCs) were derived from embryonic fibroblasts by overexpressing the Yamanaka factors Oct4, Sox2, Klf4 and c-Myc for 32 consecutive days. iPSCs were isolated by RNA FACS (for endogenous Sox2) from a heterogeneous reprogramming culture and transcriptionally compared with (1) iPSCs stabilized in 2i medium (iPS-2i) and (2) iPSCs stabilized in co-culture with mouse embryonic fibroblasts (iPS-MEF)

2014-03-20 | GSE55671 | GEO

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