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Differentiation of Human Embryonic Stem Cells under Hypoxia Conditions

ABSTRACT: Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21% O2) as somatic cells. We hypothesized that O2 levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1% or 5% O2) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O2 levels; after 24 hours at 5% O2, more than 50% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction. 26 samples in a time course experiment. Gene expression is measured at 5 different time points and under 3 different oxygen levels. Two control samples are provided.

ORGANISM(S): Homo sapiens

SUBMITTER: david montaner

PROVIDER: E-GEOD-37761 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Differentiation of Human Embryonic Stem Cells under Hypoxia Conditions

Project description:Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21% O2) as somatic cells. We hypothesized that O2 levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1% or 5% O2) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O2 levels; after 24 hours at 5% O2, more than 50% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.

2012-05-05 | GSE37761 | GEO

miRNA profiling of human saphenous vein pericyte exosomes

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Role of miRNAs in the differentiation of human embryonic stem cells to an endothelial cell lineage

Project description:To assess changes in the miRNA-ome during the early stages of endothelial differentiation, the expression of mature human miRNAs at days 2, 4 and 10 of endothelial differentiation (vs pluripotent time-matched samples) in SA461 hESC cell line was analysed in a two-channel microarray. Expression of the pluripotency-associated miRNAs miR-302a – d and miR-372 and miR-373 was significantly suppressed with progression of differentiation. The expression of miR-99b, miR-181a and miR-181b was, in contrast, increased in a time- and differentiation-dependent manner compared to time-matched pluripotent samples. The expression profiles were validated and good concordance was observed between microarray, Q-PCR and Northern blot analysis. This experiment includes a total of 28 samples which are divided in to 3 groups, each with 4 biological repeats: group 1, Parental pluripotent hESC control sample. group 2, time-matched pluripotent hESC control samples. Group 3, hESC cells directed toward endothelial differentiation at time points 2 days, 4 days and 10 days.

2012-01-01 | E-GEOD-33675 | biostudies-arrayexpress

Comparative analysis from hESC from different developmental sources of derivation

Project description:Whole genome expression analysis reveals that single blastomeres from day-3 human embryos and blastocysts show unique gene signature, thus hESC derived from these two developmental sources might show differential gene expression profile. Comparative gene expression analysis has revealed that no significant differences exist between hESCs derived from blastomeres versus those obtained from ICMs, suggesting that pluripotent hESCs involve a new developmental progression. hESC derived from single blastomeres (VAL-10B and VAL-11B) and from ICM (VAL-5, -7, and -8) were compared by global gene expression

2012-11-27 | E-GEOD-42520 | biostudies-arrayexpress

Transcriptional dynamics of pluripotent stem cell derived endothelial cell differentiation revealed by single cell RNA-Seq.

Project description:Aims: Pluripotent stem cell-derived endothelial cell products possess therapeutic potential in ischemic vascular disease. However, the factors that drive endothelial differentiation from pluripotency and cellular specification are largely unknown. The aims of this study were to use single cell RNA sequencing (scRNA-seq) to map the transcriptional landscape and cellular dynamics of directed differentiation of human embryonic stem cell-derived endothelial cells (hESC-EC), and to compare these cells to mature endothelial cells from diverse vascular beds.Methods and Results: A highly efficient directed 8-day differentiation protocol was used to generate a hESC-derived endothelial cell product (hESC-ECP), in which 66% of cells coexpressed CD31 and CD144. We observed largely homogeneous hESC and mesodermal populations at days 0 and 4 respectively, followed by a rapid emergence of distinct endothelial and mesenchymal populations. Pseudotime trajectory identified transcriptional signatures of endothelial commitment and maturation during the differentiation process. Concordance in transcriptional signatures was verified by scRNA-seq analysis using both a second hESC line RC11, and an alternative hESC-EC differentiation protocol. In total 105,727 cells were subjected to scRNA-seq analysis. Global transcriptional comparison revealed a transcriptional architecture of hESC-EC that differs from freshly isolated and cultured human endothelial cells and from organ-specific endothelial cells. Conclusions: A transcriptional bifurcation into endothelial and mesenchymal lineages was identified, as well as novel transcriptional signatures underpinning commitment and maturation. The transcriptional architecture of hESC-ECP was distinct from mature and foetal human EC.

2019-06-10 | GSE131736 | GEO

The Role of Endothelial Autocrine NRG1/ERBB4 Signaling in Cardiac Remodeling

Project description:Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (Ecs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of ERBB4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC–specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 weeks. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (Ang II) or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis and capillary density. In general, no major differences between EC–specific Erbb4 knockout mice and control littermates were observed. However, 8 weeks following TAC both myocardial hypertrophy and fibrosis were attenuated by EC–specific Erbb4 deletion, albeit these responses were normalized after 20 weeks. Similarly, 4 weeks after Ang II treatment myocardial fibrosis was less pronounced compared to control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatio-temporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury.

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Effects of Post-Myocardial Infarction Heart Failure on the Bone Vascular Niche (Mouse Data)

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2021-05-13 | E-MTAB-10448 | biostudies-arrayexpress

Effects of Post-Myocardial Infarction Heart Failure on the Bone Vascular Niche (Human Data)

2021-05-11 | E-MTAB-10432 | biostudies-arrayexpress

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2017-03-01 | GSE92965 | GEO

ncRNA (non-coding RNA) signature in endothelial cells during hypoxia

Project description:To define ncRNA expression in hypoxic endothelial cells, we applied pro-angiogenic hypoxia to cultured endothelial cells. Afterwards total RNA was isolated and underwent genechip analysis. HUVECs were subjected to normoxic or hypoxic (0.1-0.2% O2) cell culture conditions.

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