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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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).

ORGANISM(S): Mus musculus

SUBMITTER: Yasuharu Ueno

PROVIDER: E-GEOD-46631 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2013-07-01 | GSE46631 | GEO

Populus (P. tremula X tremuloides-'T89) Lipidbody proteome

Project description:Seed lipid bodies (LB), previously viewed as paradigmatic, possess a restricted proteome and serve carbon and energy storage. Albeit present in minute quantities, LBs are widespread in post-germinative tissues, where they display vigorous movement, mediate transient organellar interactions, and shuttle enzymes, and signaling molecules. Storage as well as motility and signaling are relevant in shoot meristems of woody perennials, which ahead of winter produce buds that like seeds establish dormancy, dehydrate, express OLEOSIN genes and accumulate LBs. Unlike seeds, buds do not completely desiccate and LBs retain potential signaling functions. Here, we mapped bud LB production under dormancy-inducing conditions. We found that over an 8-week period LBs enlarged significantly. Concomitantly, three major OLEOSIN family genes were transiently upregulated at the start of bud formation, while in their wake expression of lipid biosynthesis gene DGAT1a/b and lipase gene SDP1a/b increased. In parallel, LDAPa/b, LDAP2a, and LDAP3a/b were upregulated, especially LDAP1b. All LDAPs were localized to LBs. The conclusion that OLEOSINs were replaced by LDAPs was supported by the finding that PUX10a, PUX10b and CDC498A1, involved in OLESOSIN ubiquitination and degradation, were significantly upregulated. Our proteomic analysis identified 723 putative LB proteins. These included LB-anchored Caleosin and LDIP, peripherally associated LDAP1/3 and OBL1, and numerous proteins that reflect storage, transport, organellar interaction, opportunistic cargo and contaminants. There is a significant overlap with proteins identified earlier in plasmodesmal proteomes. Collectively, the data support a model in which LBs are part of a pre-installed mechanism that serves dormancy release, survival through winter and regrowth.

2021-06-29 | PXD020099 | Pride

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

Multilineage communication regulates human liver bud self-organization from pluripotency II

Project description:Conventional 2-D differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. 3-D organoids generate complex organ-like tissues, however it is unclear how heterotypic interactions impact lineage identity. Here we use single-cell RNA-seq to reconstruct hepatocyte-like lineage progression from pluripotency in 2-D culture. We then derive 3-D liver bud (LB) organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during LB development. We find that LB hepatoblasts diverge from the 2-D lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark 3-D LBs against fetal and adult human liver scRNA-seq data, and find a striking correspondence between the 3-D LB and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signaling in LBs, and show that VEGF crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.

2017-06-21 | GSE96981 | GEO

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

2015-11-05 | GSE74662 | GEO

An in vitro human liver model by iPSC-derived parenchymal and non-parenchymal cells

Project description:We have established culture systems to generate liver progenitor cells (LPCs), liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs) from hiPSCs. Then, we established co-culture system of hiPSC-derived liver cells and performed RNA-seq of hiPSC-derived liver model.

2017-07-27 | GSE98710 | GEO

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

Comparison of miRNA expression profilings between hESCs and hiPSCs

Project description:It remains controversial whether human induced pluripotent stem cells (hiPSCs) are distinct from human embryonic stem cells (hESCs) in their molecular signatures and differentiation properties. We examined the gene expression and DNA methylation of 49 hiPSC and 10 hESC lines and identified no molecular signatures that distinguished hiPSCs from hESCs. Comparisons of the in vitro directed neural differentiation of 40 hiPSC and four hESC lines showed that most hiPSC clones were comparable to hESCs. However, in seven hiPSC clones, significant amount of undifferentiated cells persisted even after neural differentiation and resulted in teratoma formation when transplantated into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression of several genes, including those expressed from long terminal repeats of human endogenous retroviruses. These data demonstrated that many hiPSC clones are indistinguishable from hESCs, while some defective hiPSC clones need to be eliminated prior to their application for regenerative medicine. We extracted total RNA from 10 hESCs, 49 hiPSCs, 2 hECCs, 6 somatic cells and 3 cancer cell lines and hybridized them to Agilent miRNA expression microarrays.

2013-12-03 | E-GEOD-42446 | biostudies-arrayexpress

Comparison of gene expression profilings between SFEBq differentiation-defective clones and good clones

Project description:It remains controversial whether human induced pluripotent stem cells (hiPSCs) are distinct from human embryonic stem cells (hESCs) in their molecular signatures and differentiation properties. We examined the gene expression and DNA methylation of 49 hiPSC and 10 hESC lines and identified no molecular signatures that distinguished hiPSCs from hESCs. Comparisons of the in vitro directed neural differentiation of 40 hiPSC and four hESC lines showed that most hiPSC clones were comparable to hESCs. However, in seven hiPSC clones, significant amount of undifferentiated cells persisted even after neural differentiation and resulted in teratoma formation when transplantated into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression of several genes, including those expressed from long terminal repeats of human endogenous retroviruses. These data demonstrated that many hiPSC clones are indistinguishable from hESCs, while some defective hiPSC clones need to be eliminated prior to their application for regenerative medicine. We extracted total RNA from 10 hESCs and 40 hiPSCs, and hybridized them to Agilent gene expression microarrays.

2013-12-03 | E-GEOD-42452 | biostudies-arrayexpress

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