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Chemically defined and growth factor-free system for highly efficient endoderm induction of human pluripotent stem cells [ATAC-seq]

ABSTRACT: Definitive endoderm (DE) derived from human pluripotent stem cells (hPSCs) holds great promise for cell-based therapies and drug discovery. However, current DE differentiation methods required undefined components and/or expensive recombinant proteins, limiting their scalable manufacture and clinical use. Homogeneous DE differentiation in defined and recombinant protein-free conditions remains a major challenge. Here, by systematic optimization and high-throughput screening, we report a fully synthetic, small molecule-based defined system that contains only four components (4C), enabling highly efficient and cost-effective DE specification of hPSCs in the absence of recombinant proteins. 4C-induced DE can differentiate into functional hepatocytes, lung epithelium, and pancreatic β cells in vitro and multiple DE-derivatives in vivo. Genomic accessibility analysis reveal that 4C reconfigures chromatin architecture to allow key DE transcription-factor binding and identify TEAD3 as a novel key DE regulator. This system may facilitate mass production of mature DE-derivatives for drug discovery, disease modelling, and cell therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274662 | GEO | 2024/11/26

REPOSITORIES: GEO

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Chemically defined and growth factor-free system for highly efficient endoderm induction of human pluripotent stem cells [RNA-seq]

Project description:Definitive endoderm (DE) derived from human pluripotent stem cells (hPSCs) holds great promise for cell-based therapies and drug discovery. However, current DE differentiation methods required undefined components and/or expensive recombinant proteins, limiting their scalable manufacture and clinical use. Homogeneous DE differentiation in defined and recombinant protein-free conditions remains a major challenge. Here, by systematic optimization and high-throughput screening, we report a fully synthetic, small molecule-based defined system that contains only four components (4C), enabling highly efficient and cost-effective DE specification of hPSCs in the absence of recombinant proteins. 4C-induced DE can differentiate into functional hepatocytes, lung epithelium, and pancreatic β cells in vitro and multiple DE-derivatives in vivo. Genomic accessibility analysis reveal that 4C reconfigures chromatin architecture to allow key DE transcription-factor binding and identify TEAD3 as a novel key DE regulator. This system may facilitate mass production of mature DE-derivatives for drug discovery, disease modelling, and cell therapy.

2024-11-26 | GSE274488 | GEO

Heparin promotes cardiac differentiation of human pluripotent stem cells in chemically defined albumin-free medium enabling consistent manufacture of cardiomyocytes

Project description:Cardiomyocytes can be differentiated from human pluripotent stem cells (hPSCs) in defined conditions, but efficient and consistent cardiomyocyte differentiation often requires expensive reagents such as B27 supplement or recombinant albumin. Using a chemically defined albumin-free (E8 basal) medium, we identified heparin as a novel factor that significantly promotes cardiomyocyte differentiation efficiency, and developed an efficient method to differentiate hPSCs into cardiomyocytes. The treatment of heparin helped cardiomyocyte differentiation consistently reach at least 80% purity (up to 95%) from more than 10 different hPSC lines in chemically defined DMEM/F-12 based medium on either Matrigel or defined matrices like Vitronectin and Synthemax. One of heparinâs main functions was to act as a WNT modulator that helped promote robust and consistent cardiomyocyte production. Our study provides an efficient, reliable, and cost-effective method for cardiomyocyte derivation from hPSCs that can be used for potential large-scale drug screening, disease modeling, and future cellular therapies. 12 human pluripotent stem cells (hPSCs) at three different cardiac differentiation times (0 Days, 3 Days, 6 Days, 10 Days) under different culture conditions (+/- Heparin, +/- IWP2).

2016-07-28 | E-GEOD-81711 | biostudies-arrayexpress

Heparin promotes cardiac differentiation of human pluripotent stem cells in chemically defined albumin-free medium enabling consistent manufacture of cardiomyocytes

Project description:Cardiomyocytes can be differentiated from human pluripotent stem cells (hPSCs) in defined conditions, but efficient and consistent cardiomyocyte differentiation often requires expensive reagents such as B27 supplement or recombinant albumin. Using a chemically defined albumin-free (E8 basal) medium, we identified heparin as a novel factor that significantly promotes cardiomyocyte differentiation efficiency, and developed an efficient method to differentiate hPSCs into cardiomyocytes. The treatment of heparin helped cardiomyocyte differentiation consistently reach at least 80% purity (up to 95%) from more than 10 different hPSC lines in chemically defined DMEM/F-12 based medium on either Matrigel or defined matrices like Vitronectin and Synthemax. One of heparin’s main functions was to act as a WNT modulator that helped promote robust and consistent cardiomyocyte production. Our study provides an efficient, reliable, and cost-effective method for cardiomyocyte derivation from hPSCs that can be used for potential large-scale drug screening, disease modeling, and future cellular therapies.

2016-07-28 | GSE81711 | GEO

Transcriptomics during the differentiation of human pluripotent stem cells to hepatocyte-like cells

Project description:Human pluripotent stem cells (hPSCs) can differentiate into all cell types in the body that may replace current cell sources applied in regenerative medicine, cell therapy, drug discovery and development and general research. Human PSC-derived hepatocyte-like cells (HLCs) have the potential to replace primary hepatocytes and other cell models applied in liver disease treatment and drug discovery and development. These cells share many features with their in vivo counterparts however, the generation of fully functional hPSC-derive HLCs is still lacking, which prevent their application in the previously mentioned fields. This study followed the transcriptome dynamics during the differentiation of hPSC-derived HLCs at definitive endoderm, hepatoblast, early HLC and late HLC developmental stages and the controls hPSCs and human liver tissues which consists of at least 70% hepatocytes. The aim is to reveal expression deviations between hPSC-derived hepatocytes and their in vivo counterparts that may contribute to the modification of differentiation protocols to generate fully functional hepatocytes.

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Enhanced CLIP uncovers IMP protein-RNA targets in human pluripotent stem cells important for cell adhesion and survival [eCLIP-Seq]

Project description:Human pluripotent stem cells (hPSCs) require precise control of post-transcriptional RNA networks to maintain proliferation and survival. Using a recently developed enhanced UV crosslinking and immunoprecipitation (eCLIP) approach, we identify RNA targets of the IMP/IGF2BP family of RNA-binding proteins in hPSCs. At the broad region- and binding site-level IMP1 and IMP2 show reproducible binding to a large and overlapping set of 3'UTR-enriched targets. RNA Bind-N-Seq applied to recombinant full-length IMP1 and IMP2 reveals CA-rich motifs that are enriched in eCLIP-defined binding sites. We observe that IMP1 loss in hPSCs recapitulates IMP1 phenotypes, including a reduction in cell adhesion and an increase in cell death. For cell adhesion, in hPSCs we find IMP1 maintains levels of integrin mRNA, specifically regulating RNA stability of ITGB5. Additionally, we show IMP1 can be linked to hPSC survival via direct target BCL2. Thus, transcriptome-wide binding profiles identify hPSC targets modulating well-characterized IMP1 roles. eCLIP-seq was performed in biological replicate for IGF2BP1/IMP1 and IGF2BP2/IMP2, as well as one replicate each for IGF2BP3/IMP3, RBFOX2, and an IgG control. Each sample has a size-matched input control for analysis

2016-04-07 | E-GEOD-78507 | biostudies-arrayexpress

Enhanced CLIP uncovers IMP protein-RNA targets in human pluripotent stem cells important for cell adhesion and survival [RNA-Seq]

2016-04-07 | E-GEOD-78508 | biostudies-arrayexpress

Functional Cardiac Fibroblasts Derived from Human Pluripotent Stem Cells via Second Heart Field Progenitors

Project description:Cardiac fibroblasts (CFs) play critical roles in heart development, homeostasis, and disease. The limited availability of human CFs from native heart impedes investigations of CF biology and their role in disease. Human pluripotent stem cells (hPSCs) provide a highly renewable and genetically defined cell source, but efficient methods to generate CFs from hPSCs have not been described. Here, we show differentiation of hPSCs using sequential modulation of Wnt and FGF signaling to generate second heart field progenitors that efficiently give rise to hPSC-CFs. The hPSC-CFs resemble native heart CFs in cell morphology, proliferation, gene expression, fibroblast marker expression, production of extracellular matrix and myofibroblast transformation induced by TGFβ1 and angiotensin II. Furthermore, hPSC-CFs exhibit a more embryonic phenotype when compared to fetal and adult primary human CFs. Co-culture of hPSC-CFs with hPSC-derived cardiomyocytes distinctly alters the electrophysiological properties (EP) of the cardiomyocytes compared to co-culture with dermal fibroblasts (DFs). The hPSC-CFs provide a powerful cell source for research, drug discovery, precision medicine, and therapeutic applications in cardiac regeneration.

2019-02-08 | GSE126260 | GEO

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Project description:Human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) hold great promise for liver disease modeling, drug discovery, drug toxicity screens, or even regenerative therapies. Yet, several hurdles still need to be overcome, including among others decrease in the cost of goods to generate HLCs and automation of the differentiation process. We here describe that use of an automated liquid handling system results in highly reproducible HLC differentiation from hPSCs. This enabled us to screen 92 chemicals to replace expensive growth factors at each step of the differentiation protocol to reduce the cost of goods of the differentiation protocol by approximately 79%. In addition, we also evaluated several recombinant extracellular matrices (ECM) to replace Matrigel. We demonstrated that differentiation of hPSCs on Laminin-521 using an optimized small molecule combination resulted in HLCs that were transcriptionally identical to HLCs generated using current growth factor combinations. In addition, the HLCs created using the optimized small molecule combination also secreted similar concentrations of albumin and urea, and relatively low concentrations of alfa-fetoprotein (AFP), displayed similar CYP3A4 functionality and a similar drug toxicity susceptibility as HLCs generated with growth factor cocktails. The broad applicability of the new differentiation protocol was demonstrated for four different hPSC lines. This allowed the creation of a scalable, xeno-free, and cost-efficient hPSC-derived HLC culture, suitable for high throughput disease modeling and drug screenings, or even for the creation of HLCs for regenerative therapies.

2024-02-26 | GSE207569 | GEO

Deriving Schwann Cells from hPSCs Enable Disease Modeling and Drug Discovery for Diabetic Peripheral Neuropathy

Project description:Deriving Schwann Cells from hPSCs Enable Disease Modeling and Drug Discovery for Diabetic Peripheral Neuropathy

| PRJNA802029 | ENA

Transferrin improved the generation of cardiomyocyte from human pluripotent stem cells for myocardial infarction repair

Project description:Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for the repair of the injured heart, but optimal cell production in a fully chemically defined and cost-effective system is essential for the efficacy and safety of cell transplantation therapies. In this study, we provided a simple and efficient strategy for cardiac differentiation from hPSCs and performed functional evaluation in a rat model of myocardial infarction. Using a chemically defined medium including four components, recombinant human albumin, ascorbic acid, human transferrin, and RPMI 1640, we developed a manageable and cost-effective protocol for robust generation of CMs from hPSCs. Interestingly, the addition of transferrin helped hPSCs to transit from TeSR-E8 medium to the simple cardiac differentiation medium and successfully initiated mesoderm differentiation without significant cell death. The CM generation efficiency was up to 85% based on cTnT expression. We performed transcriptome profiling from differentiation day 0 to 35, and characterized interesting dynamic change of cardiac genes. CMs derived from transferrin supplemented simple medium have similar transcriptome and the maturation level compared to cardiomyocytes generated in B27 minus insulin medium as well as their in vivo counterparts. Importantly, after transplantation, hPSC derived CMs survived in the infarcted rat heart, significantly improved the physiological function and reduced fibrosis. Our study offers an easy-to-use and cost-effective method for cardiac differentiation and facilitates the translational application of hPSC-derived CMs for heart repair.

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