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Massive and reproducible production of liver buds entirely from human pluripotent stem cells

ABSTRACT: Organoid technology provides a revolutionary paradigm towards therapy, yet to be applied in humans mainly because of the reproducibility and scalability challenges. Here, we overcome these limitations by evolving scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC). By conducting massive ‘reverse’ screen experiments, we identified effective triple progenitor populations for generating liver buds in a highly reproducible manner: hepatic endoderm, endothelial and septum mesenchyme progenitors. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass-producing homogenous and miniaturized liver buds on a clinically relevant large scale (>108-cell scale). Vascularized and functional liver tissues generated entirely from iPSC significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacture platform for multi-cellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106465 | GEO | 2017/11/03

SECONDARY ACCESSION(S): PRJNA416927

REPOSITORIES: GEO

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Human iPSC derived posterior gut progenitors are expandable and capable of forming gut and liver organoids

Project description:Organoid technology provides a revolutionary paradigm towards therapy, yet to be applied in humans mainly because of the reproducibility and scalability challenges. Here, we overcome these limitations by evolving scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC). By conducting massive ‘reverse’ screen experiments, we identified effective triple progenitor populations for generating liver buds in a highly reproducible manner: hepatic endoderm, endothelial and septum mesenchyme progenitors. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass-producing homogenous and miniaturized liver buds on a clinically relevant large scale (>108-cell scale). Vascularized and functional liver tissues generated entirely from iPSC significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacture platform for multi-cellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations.

2018-01-10 | GSE108937 | GEO

Hepatic differentiation of liver organoids

Project description:We analyzed gene expression profiles of self-organizing, multi-cellular, 3D liver organoids derived by co-culture of induced Pluripotent Stem Cell and stromal progenitors. We report the RNA-seq results of liver organoid at day0, day2, day4, day6 of co-culture. We also report RNA-seq results of constituent of the liver organoid, which are human iPSC at hepatic specification stage, human Mesenchymal stem cells derived from bone marrow, human umbilical vein endothelial cell. As controls, we also report RNS-seq results of un-differentiated human iPSC, human iPSC at definitive endoderm stage, human liver tissue, and primary cultured human hepatocytes isolated from unused donor livers.

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Integrative analysis of transcriptomic and epigenomic dynamics of liver organoids using single cell RNA-seq and ATAC-seq.

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2023-10-16 | GSE159557 | GEO

Massive and reproducible production of liver buds entirely from human pluripotent stem cells

Project description:Massive and reproducible production of liver buds entirely from human pluripotent stem cells

| PRJNA416927 | ENA

Generation of Brain Region-specific Organoids using a Miniaturized Spinning Bioreactor and Modelling ZIKV Exposure

Project description:Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability and tissue heterogeneity limit accessibility and broad applications of current organoid technologies. Here we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and importantly, a distinct human-specific outer radial glia cell layer. We have also developed protocols to generate midbrain and hypothalamic organoids. Finally, we employed this forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed that preferential, productive ZIKA infection of cortical neural progenitors leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell layer volume that resembles microcephaly. Together, our brain region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and diseases, and for compound testing.

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Bulk RNA-seq of MilliporeSigma 3DGro human patient-derived gastrointestinal organoid lines compared to SCC300 human iPSC-derived colon organoid line

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2022-03-31 | E-MTAB-11557 | biostudies-arrayexpress

Highly reproducible and cost-effective one-pot organoid differentiation using a novel platform based on PF-127 triggered spheroid assembly

Project description:Using a novel platform based on the findings that Pluronic F-127 (PF-127) could trigger highly uniform spheroid assembly, we develop a one-pot organoid differentiation strategy. Using our strategy, we successfully generate cortical, nephron, hepatic, and lung organoids with improved reproducibility compared to previous methods while reducing the original costs by 80-95%. In addition, we adapt our platform to microfluidic chips allowing automated culture. We showcase that our platform can be applied to tissue-specific screening, such as drug toxicity and transfection reagents testing. And, we generate NEAT1 knockout tissue-specific organoids and show NEAT1 modulates multiple signaling pathways fine-tuning the differentiation of nephron and hepatic organoids and suppresses immune responses in cortical organoids. In summary, our strategy provides a powerful platform for advancing organoid research and studying human development and diseases.

2023-08-08 | GSE240256 | GEO

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2019-10-16 | E-MTAB-8083 | biostudies-arrayexpress

A Highly Phenotyped Open Access Repository of Alpha-1 Antitrypsin Deficiency Pluripotent Stem Cells

Project description:We profiled the global transcriptomes of 10 featured AATD-patient specific iPSC that underwent directed differentiation towards a hepatic and lung lineage. We used digital gene expression (DGE), a platform for high-fidelity RNA sequencing, and in addition to differentiated iPSC-derived cell types mentioned above (iHeps and iPSC-Lung progenitors), we also collected RNA from undifferentiated iPSCs and from a panel of primary adult human hepatocytes (PHH) for comparison.

2020-07-27 | GSE140732 | GEO

Robust, long-term culture of endoderm derived hepatic organoids (eHEPOs) for disease modeling

Project description:Many liver pathologies ranging from cancer to genetic metabolic diseases are amenable to cellular replacement therapies. One of the main difficulties associated with cellular therapy approaches is the generation and expansion of mature autologous hepatocytes. The ability to derive patient-specific induced pluripotent stem cells (iPSCs) have solved the problem of generating autologous cells but differentiation and expansion of mature hepatocytes remain a challenge. Here, we report the generation of human iPSC-derived hepatic organoid (eHEPO) culture system for producing functional hepatocytes using EpCAM-positive endodermal cells as an intermediate. eHEPOs can be produced within two weeks and expanded long-term without any lose of differentiation capacity to mature hepatocyte (>12 months with passage number 25) and are resilient to freeze-thaw cycles. The hepatic identity of eHEPOs was confirmed by morphological analyses, expression of mature hepatocyte markers and in vitro functional assays. Extensive global transcriptome analyses of all intermediate stages demonstrated the stepwise differentiation iPSCs to mature hepatocytes in endoderm-derived organoids. Finally, starting form patient-specific iPSCs, we created an organoid-based model of Citrullinemia type 1, an inherited urea cycle disorder caused by mutations in the argininosuccinate synthetase (ASS1) enzyme. The disease-related ammonia accumulation phenotype in eHEPOs could be reversed by the overexpression of the wild type ASS1 gene which also indicated that this model is amenable to genetic manipulation. Our results demonstrate that iPSC-derived EpCAM-positive endodermal cells are excellent cell sources to generate patient-specific hepatic organoids in a fast and efficient manner.

2019-09-01 | GSE120145 | GEO

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