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Dox-regulated Notch4 overexpression in mouse ES cells redirects hemagioblasts to a cardiac fate.

ABSTRACT: Previous studies have demonstrated that distinct progenitor subpopulations of mesoderm display tissue specific and vascular potential: hemangioblasts, a progenitor population capable of generating cells of the hematopoietic, endothelial and vascular smooth muscle lineages, and a multipotential progenitor capable of generating progeny of the cardiac, endothelial and vascular smooth muscle lineages. Each of these populations is characterized by co-expression of brachyury (Bry) and Flk-1, although the hemangioblast population is established before the cardiovascular progenitors in ES cell differentiation cultures (e.g. d3.5 for hemagioblast, versus d4.5 for cardiovascular progenitors). To investigate the role of Notch signalling in the establishment of cardiac lineages, we used a tet-inducible ES cell line (Ainv18) engineered to express an activated form of the Notch4 receptor following doxycycline treatment. This line also expresses a GFP cDNA from the Bry locus. Following 3.0-3.5 days of serum stimulation, three distinct populations based on Flk-1 and GFP expression are observed: Bry-GFP-/Flk-1-, Bry-GFP+/Flk-1- and Bry-GFP+/Flk-1+ cells. Previous studies have shown that the Bry-GFP+/Flk-1+ population contains hemangioblasts, whereas the Bry-GFP+/Flk-1- population displays cardiac potential.

ORGANISM(S): Mus musculus

PROVIDER: GSE12425 | GEO | 2008/09/28

SECONDARY ACCESSION(S): PRJNA113749

REPOSITORIES: GEO

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Dox-regulated Notch4 overexpression in mouse ES cells redirects hemagioblasts to a cardiac fate.

Project description:Previous studies have demonstrated that distinct progenitor subpopulations of mesoderm display tissue specific and vascular potential: hemangioblasts, a progenitor population capable of generating cells of the hematopoietic, endothelial and vascular smooth muscle lineages, and a multipotential progenitor capable of generating progeny of the cardiac, endothelial and vascular smooth muscle lineages. Each of these populations is characterized by co-expression of brachyury (Bry) and Flk-1, although the hemangioblast population is established before the cardiovascular progenitors in ES cell differentiation cultures (e.g. d3.5 for hemagioblast, versus d4.5 for cardiovascular progenitors). To investigate the role of Notch signalling in the establishment of cardiac lineages, we used a tet-inducible ES cell line (Ainv18) engineered to express an activated form of the Notch4 receptor following doxycycline treatment. This line also expresses a GFP cDNA from the Bry locus. Following 3.0-3.5 days of serum stimulation, three distinct populations based on Flk-1 and GFP expression are observed: Bry-GFP-/Flk-1-, Bry-GFP+/Flk-1- and Bry-GFP+/Flk-1+ cells. Previous studies have shown that the Bry-GFP+/Flk-1+ population contains hemangioblasts, whereas the Bry-GFP+/Flk-1- population displays cardiac potential. Bry-GFP+/Flk-1+ cells, sorted from EB's derived from ES cell differentiation cultures exposed to serum for 3.5 days, were allowed to reaggregate for 24 in the presence or absence of doxycycline, and the total RNA harvested at 4, 12, 24, 48, and 96 hours post Dox induction for microarray analysis. The induced populations were compared to non-induced population harvested at the same time points.

2010-09-15 | E-GEOD-12425 | biostudies-arrayexpress

Endothelin-1 supports clonal derivation and expansion of cardiovascular progenitors derived from human embryonic stem cells

Project description:Coronary arteriogenesis is a central step in cardiogenesis, requiring coordinated generation and integration of endothelial (EC) and vascular smooth muscle cells (SM). At present, it is unclear whether the cell fate program of cardiac progenitors to generate complex muscular or vascular structures is entirely cell autonomous. Here we demonstrate the intrinsic ability of vascular progenitors to develop and self-organize into cardiac tissues by clonally isolating and expanding second heart field (SHF) cardiovascular progenitors (CVPs) using WNT3A and Endothelin-1 (EDN1) human recombinant proteins. Progenitor clones undergo long-term expansion and differentiate primarily into endothelial and smooth muscle cell lineages in vitro, and contribute extensively to coronary-like vessels in vivo, forming a functional human-mouse chimeric circulatory system. Our study identifies EDN1 as a key factor towards the generation and clonal derivation of ISL1+ vascular intermediates, and demonstrates for the first time, the intrinsic cell-autonomous nature of these progenitors to differentiate and self-organize into functional vasculatures in vivo. The HumanHT-12 v4 BeadChip (Illumina) was used to analyse paracrine factors produced by sub-regions of the fetal heart, followed by pairing the paracrine factors present in these specific regions with corresponding receptors that are highly expressed in uncommitted cardiovascular progenitor cells.

2015-12-15 | E-GEOD-75985 | biostudies-arrayexpress

Endothelin-1 supports clonal derivation and expansion of cardiovascular progenitors derived from human embryonic stem cells

2015-12-15 | GSE75985 | GEO

Single cell sequencing of 43,168 cells during the differentiation from human induced pluripotent stem cells to cardiomyocytes

Project description:Differentiation into diverse cell lineages requires orchestration of gene regulatory networks guiding cell fate choices. Genetic factors acting through changes in transcriptional levels can contribute to cardiovascular disease risk by impacting early stages of development and have cell type-specific effects. We set out to characterize lineage trajectory progression of subpopulations and identify potential disease-related genes by examining their expression changes in single cells during early stages of cardiac lineage specification. Using 43,168 single-cell transcriptomes, we developed novel classification and trajectory analysis methods to dissect cellular composition and gene networks across five discrete time points underlying lineage derivation of mesoderm, definitive endoderm, vascular endothelium, cardiac precursors, and definitive cell types that comprise cardiomyocytes and a previously unrecognized cardiac outflow tract population.

2018-10-06 | E-MTAB-6268 | biostudies-arrayexpress

Early Multipotent Cardiovascular Progenitors Derived from Pluripotent Stem Cells Engraft in Postmyocard Infarted Primate

Project description:During embryogenesis, the cardiac cell fate is acquired as early as gastrulation. There is compelling evidence that embryonic stem cells (ESC) can recapitulate early steps in cardiogenesis. Identification from human pluripotent stem cells of early cardiovascular cell progenitors, at the origin of the first cardiac lineage, would shed light on human normal and pathological cardiogenesis and would pave the way toward cell therapy for cardiac degenerative diseases. Here, we report the isolation, and a phenotypic characterisation of an early Oct-4+, SSEA-1+, Mesp1+ population of cardiovascular progenitors derived from human pluripotent stem cells. This multipotential progenitor features the capability to generate cardiomyocytes as well as smooth muscle and endothelial cells. We further bring a proof of concept that these progenitors can be used in cardiac regenerative medicine as allografted in infarcted non human primate myocardium, they differentiate in ventricular myocytes without any adverse effect. One RNA sample from HUESC-POU5F1 was compared in dye-swap to undifferentiated HUESC. Three distinct RNA samples from BMP2-induced SSEA1+ cells were compared in dye-swap to paired remaining SSEA1-. Reference samples correspond to undifferentiated HUESC and to SSEA1 negative cells, respectively. population respectivement.

2011-02-08 | E-GEOD-20230 | biostudies-arrayexpress

Cardiac mesoderm induction by Tbx6 without exogenous factors

Project description:Cardiac mesoderm, a precursor for all cardiovascular lineages, is a promising cell source for basic research and clinical applications. BMP/Nodal/Wnt signaling induces cardiac mesoderm in embryonic stem cells (ESCs); however the molecular mechanism is unclear and the differentiation protocols are labor-intensive. Identification of a master regulator that induces cardiac mesoderm is needed. Here we found that Tbx6 directly reprogrammed mouse fibroblasts into cardiac mesoderm-like cells, which differentiated into cardiomyocytes and smooth muscle cells with addition of lineage-specific transcription factors. In mouse ESCs, BMP/Activin (Nodal) induced Tbx6 in cardiac mesoderm, while inhibition of Tbx6 blocked differentiation into cardiac mesoderm and cardiomyocytes. Conversely, transient expression of Tbx6 induced cardiac mesoderm in ESCs without exogenous factors, and generated all cardiovascular lineages. Mechanistically, Tbx6 directly upregulated Mesp1, inhibited Sox2, and activated BMP/Nodal/Wnt signaling to induce cardiac mesoderm. Thus, Tbx6 acts as a key regulator for cardiac mesoderm induction, and our findings provide new insights into the mechanism of cardiovascular differentiation.

2018-10-19 | GSE89820 | GEO

Expression data from day 3 Flk-1 mesoderm between ER71 overexpressed and ER71 knockout mouse embryonic stem cell

Project description:Ets transcription factor ER71 is critical for Flk-1 mesoderm specification to different cell lineages. In this dataset, we determine to investigate the mechanisms by which ER71 regulates hematopoietic and endothelial cell versus cardiac cell lineage development. Expression of all four Flk-1+ mesoderm populations (i.e. Er71 overexpressed versus control, Er71 deficient versus control Flk-1+ mesoderm) was compared. Specifically, we sorted Flk-1+ mesoderm from day 3 differentiated embryonic stem(ES) cells, including induced Er71 and control ES cells, as well as Er71+/+ as well as Er71-/- ES cells .

2012-02-20 | E-GEOD-35793 | biostudies-arrayexpress

Sox7 regulates lineage decisions in cardiovascular progenitor cells

Project description:Specification of the mesodermal lineages requires a complex set of morphogenetic events orchestrated by interconnected signaling pathways and gene regulatory networks. The transcription factor Sox7 has critical functions in differentiation of multiple mesodermal lineages, including cardiac, endothelial, and hematopoietic. Using a doxycycline-inducible mouse embryonic stem cell (mESC) line, we have previously shown that expression of Sox7 in cardiovascular progenitor cells promotes expansion of endothelial progenitor cells. Here, we show that the ability of Sox7 to promote endothelial cell fate occurs at the expense of the cardiac lineage. Using ChIP-Seq coupled with ATAC-Seq we identify downstream target genes of Sox7 in cardiovascular progenitor cells and, by integrating these data with transcriptomic analyses, we define Sox7-dependent gene programs specific to cardiac and endothelial progenitor cells. Further, we demonstrate a protein-protein interaction between SOX7 and GATA4 and provide evidence that Sox7 interferes with the transcriptional activity of Gata4 on cardiac genes. In addition, we show Sox7 modulates WNT and BMP signaling during cardiovascular differentiation. Our data represent the first genome-wide analysis of Sox7 function and reveal a critical role for Sox7 in regulating signaling pathways that affect cardiovascular progenitor cell differentiation.

2019-07-06 | GSE133899 | GEO

Low input RNA-seq of endothelial cells sorted from tail of zebrafish larvae

Project description:To characterize the mechanism by which AML derived extracellular vesicles(EV) impaired the vascular architecture and function, EV or PBS injected flk:GFP zebrafish larvae were used for sorting endothelial cells and performing RNA-Seq. Vascular niches sustain hematopoietic stem and progenitor cells (HSPC) and are drastically remodeled in myeloid leukemia to support pathological progression. By utilizing the leukemia-xenografted zebrafish model, we identified that myeloid leukemia secreted extracellular vesicles (EVs) to impair HSPC proliferation, survival and differentiation towards lymphoid/erythroid lineages. The leukemia EVs delivered arginase-1 into venous vasculature to deplete L-arginine and cause NOS uncoupling, which catalyzes production of ROS instead of NO. The oxidative stress caused endothelial cell loss, vascular constriction and failure of secreting niche factors and supporting hematopoiesis. Our findings indicate that myeloid leukemia impaired the vascular function of supporting hematopoiesis by delivering arginase in EVs and arginase inhibition has the potential to improve normal hematopoiesis in myeloid leukemia.

2023-09-01 | GSE229261 | GEO

CD146 expression in mesenchymal stem cells is associated with vascular smooth muscle commitment

Project description:Bone-marrow mesenchymal stem cells (MSCs) are plastic adherent cells that can differentiate into various tissue lineages, including osteoblasts, adipocytes and chondrocytes. However, this progenitor property is not shared by all cells within the MSC population. In addition, MSCs vary in their proliferation capacities and expression of markers. Because of heterogeneity of CD146 expression in the MSC population, we compared CD146-/Low and CD146High cells under clonal and non-clonal (sorted MSCs) conditions to determine whether this expression is associated with specific functions. CD146-/Low and CD146High MSCs did not differ in colony-forming unit-fibroblast number, osteogenic and adipogenic differentiation or in vitro hematopoietic supportive activity. However, CD146-/Low clones proliferated slightly but significantly faster than did CD146High clones. In addition, a strong expression of CD146 molecule was associated with a commitment towards a vascular smooth muscle cell lineage with upregulation of calponin-1 expression. Thus, within a bone-marrow MSC population, certain subpopulations characterized by high expression of CD146, are committed toward a vascular smooth muscle cell lineage. Clonal MSC were selected on the basis of CD146 level at their surface (CD146Low and CD146 High) and non-clonal MSC were compared from 4 different donors.

2013-07-04 | E-GEOD-48540 | biostudies-arrayexpress

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