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Genetically engineering self-organization of human pluripotent stem cells into a liver bud-like tissue using Gata6

ABSTRACT: Human induced pluripotent stem cells (hiPSCs) have potential for personalized and regenerative medicine. While most methods of utilizing these cells have focused on deriving homogenous populations of specialized cells, there has been modest success in producing hiPSC-derived organotypic tissues or organoids. Here we present a novel approach for generating and then co-differentiating hiPSC-derived progenitors. With a genetically engineered pulse of GATA6 expression, we initiate rapid emergence of all three germ layers as a complex function of GATA6 expression levels and tissue context. Within two weeks we obtain a complex tissue that recapitulates early developmental processes and exhibits a liver bud-like phenotype, including haematopoietic and stromal cells, as well as a neuronal niche. Our approach addresses two major issues in derivation of tissues from hiPSCs: using a single autologous hiPSCs as source and generating a range of stromal cells that co-develop with parenchymal cells to form complex tissues.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74662 | GEO | 2015/11/05

SECONDARY ACCESSION(S): PRJNA301104

REPOSITORIES: GEO

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Genetically engineering self-organization of human pluripotent stem cells into a liver bud-like tissue using Gata6

Project description:Human induced pluripotent stem cells (hiPSCs) have potential for personalized and regenerative medicine. While most methods of utilizing these cells have focused on deriving homogenous populations of specialized cells, there has been modest success in producing hiPSC-derived organotypic tissues or organoids. Here we present a novel approach for generating and then co-differentiating hiPSC-derived progenitors. With a genetically engineered pulse of GATA6 expression, we initiate rapid emergence of all three germ layers as a complex function of GATA6 expression levels and tissue context. Within two weeks we obtain a complex tissue that recapitulates early developmental processes and exhibits a liver bud-like phenotype, including haematopoietic and stromal cells, as well as a neuronal niche. Our approach addresses two major issues in derivation of tissues from hiPSCs: using a single autologous hiPSCs as source and generating a range of stromal cells that co-develop with parenchymal cells to form complex tissues. Gene expression profiling (microarray) of iPS cells (PGP1) at X days post- doxycycline induction of mouse Gata6. Either total cells or immunomagnetic isolation of cells with specific surface markers. Three samples per group.

2015-11-05 | E-GEOD-74662 | biostudies-arrayexpress

Vascularised and functional human liver from an iPSC-derived organ bud transplant

Project description:Critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from induced pluripotent stem cells (hiPSCs). Despite many reports describing functional cell differentiation, no studies have succeeded in generating a three-dimensional vascularised organ such as liver. Here, we show the generation of vascularised and functional human liver from hiPSCs by transplantation of liver buds created in vitro (hiPSC-LBs). Specified hepatic cells self-organised into three-dimensional hiPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells. Immunostaining and gene expression analyses revealed resemblance between in vitro grown hiPSC-LBs and in vivo liver buds. Human vasculatures in hiPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of hiPSC-LBs into tissue resembling the adult liver. Highly metabolic hiPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement. Comparison of liver developmental gene signatures among hiPSC-LB, hFLC-LB, human adult (30 years old) liver tissues (hALT) and mouse liver tissue (mLT) of various developmental stages (E9.5~P8weeks).

2013-07-01 | E-GEOD-46631 | biostudies-arrayexpress

Comparing Control and Schizophrenic hiPSC-derived Neurons

Project description:Schizophrenia is a debilitating neurological disorder for which no cure exists. Few defining characteristics of schizophrenic neurons have been identified and the molecular mechanisms responsible for schizophrenia are not well understood, in part due to the lack of patient material for study. Human induced pluripotent stem cells (hiPSCs) offer a new strategy for studying schizophrenia. We have created the first cell-based human model of a complex genetic psychiatric disease by generating hiPSCs from schizophrenic patients and subsequently differentiating these cells to hiPSC-derived neurons in vitro. Schizophrenic hiPSC-derived neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of schizophrenic hiPSC-derived neurons identified altered expression of many components of the cAMP and WNT signaling pathways. Key cellular and molecular elements of the schizophrenic phenotype were ameliorated following treatment of schizophrenic hiPSC-derived neurons with the antipsychotic loxapine. 3 independent differentiations (biological replicates) for each of four control and four schizophrenic patients were analyzed.

2011-05-01 | E-GEOD-25673 | biostudies-arrayexpress

Vascularised and functional human liver from an iPSC-derived organ bud transplant

2013-07-01 | GSE46631 | GEO

Comparing Control and Schizophrenic hiPSC-derived Neurons

2011-05-01 | GSE25673 | GEO

GATA6-AS1 Regulates GATA6 Expression to Modulate Human Endoderm Differentiation

Project description:Transcriptome analysis has uncovered a series of long noncoding RNAs (lncRNAs) transcribed during cell differentiation. Here, we uncovered lncRNA GATA6-AS1 is a functional lncRNA in definitive endoderm (DE) differentiation. We found GATA6-AS1 positively regulated the expression of endoderm key factor GATA6, which was different from previous reports in other biological contexts. Further investigation showed GATA6-AS1 interacted with SMAD2/3 and recruited SMAD2/3 to the promoter region of the GATA6 gene locus. In addition, overexpression of GATA6 was able to rescue the defect of DE differentiation due to the absence of GATA6-AS1, suggesting GATA6 was the functional target of GATA6-AS1 during endoderm differentiation. Ultimately, our study uncovers GATA6-AS1 is necessary for DE and pancreas differentiation, and reveals the detailed regulation mechanism between GATA6-AS1 and DE differentiation.

2020-07-26 | GSE143499 | GEO

Gene expression signature of Gata6 positive epidermal cells.

2017-05-16 | GSE62606 | GEO

CGH analyses of human induced pluripotent stem cells

Project description:Human induced pluripotent stem cells (hIPSCs) represent a unique opportunity for regenerative medicine since they offer the prospect of generating unlimited quantities of cells for autologous transplantation as a novel treatment for a broad range of disorders. However, the use of hIPSCs in the context of genetically inherited human disease will require correction of disease-causing mutations in a manner that is fully compatible with clinical applications. Genomic instability induced by reprogramming or genetic modification would be a main issue for the safe use of these cells. We analyzed primary hIPSC lines and genetically modified derivatives by array-based comparative genomic hybridization.

2011-09-01 | E-MEXP-3316 | biostudies-arrayexpress

Gene expression signature of Gata6 positive epidermal cells.

Project description:To characterize gene expression in Gata6 positive epidermal cells we analyzed a Gata6 reporter mouse in which the endogenous Gata6 promoter drives expression of mTomato. We performed flow cytometry followed by transcriptome analysis. We compared four subpopulations of telogen epidermal cells: Gata6+/Itga6+ cells, Gata6+/itga6- cells, CD34+/Itga6+ cells (which are Gata6-) and all remaining Itga6+ cells (Gata6-/CD34-). The RNA was isolated from age and sex matched mice. We compared four subpopulations of telogen epidermal cells: Gata6+/Itga6+ cells, Gata6+/itga6- cells, CD34+/Itga6+ cells (which are Gata6-) and all remaining Itga6+ cells (Gata6-/CD34-). The RNA was isolated from age and sex matched mice. Three biological replicates for each cell population were analyzed

2017-05-16 | E-GEOD-62606 | biostudies-arrayexpress

Expression data from human induced pluripotent stem cells derived retinal pigment epithelium (hiPSC-RPE)

Project description:We generated hiPSCs from patients fibloblast with retinitis pigmentosa (RP) using retrovirus and Sendai virus vectors, which we differentiated into hiPSC derived retinal pigment epithelium using two different methods (SDIA and SFEB methods). We investigated whether these hiPSC-RPE colonies, which were differentiated from various cell lines and methods, showed similar gene expression patterns to those of native RPE. We classified hiPSC-RPE, hiPSCs, and fibroblasts from RP patients, hRPE (commercially available human fetal RPE, Lonza) , ARPE19 (a human RPE cell line), and other human tissues from 54,675 probe sets using microarray data.

2014-11-03 | E-GEOD-50738 | biostudies-arrayexpress

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