Early Multipotent Cardiovascular Progenitors Derived from Pluripotent Stem Cells Engraft in Postmyocard Infarted Primate
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE20230 | GEO | 2011/02/08
SECONDARY ACCESSION(S): PRJNA124167
REPOSITORIES: GEO
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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
Project description:We performed time-dependent, genome-wide analysis to explore gene expression profiles during in vitro cardiogenesis from embryonic stem cells to cardiac progenitor cells. Total RNA was extracted from undifferentiated stem cells, early mesodermal cells, cardiac mesodermal cells and cardiac progenitor cells. As a result of cluster analysis, Cited gene family was considered as candidate genes in cardiogenesis. Cited4 gene expression was specific for early cardiogenesis and Cited4 functioned as a cell cycle controling factor for early cardiac progenitor cells. Embryoid body was formed as in vitro cardiogenesis. Total RNA was extracted from Rex1-positive undifferentiated stem cells at day 0, Bra-positive early mesodermal cells at day 4.5, Flk1-positive cardiac mesodermal cells at day 4.5 and Nkx2.5-positive cardiac progenitor cells at day 7.5.
2016-03-31 | E-GEOD-63069 | biostudies-arrayexpress
Project description:We performed time-dependent, genome-wide analysis to explore gene expression profiles during in vitro cardiogenesis from embryonic stem cells to cardiac progenitor cells. Total RNA was extracted from undifferentiated stem cells, early mesodermal cells, cardiac mesodermal cells and cardiac progenitor cells. As a result of cluster analysis, Cited gene family was considered as candidate genes in cardiogenesis. Cited4 gene expression was specific for early cardiogenesis and Cited4 functioned as a cell cycle controling factor for early cardiac progenitor cells.
2016-03-31 | GSE63069 | GEO
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
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.
2015-12-15 | GSE75985 | GEO
Project description:Self-organisation and coordinated morphogenesis of multiple cardiac lineages is essential for the development and function of the heart1-3. However, the absence of a human in vitro model that mimics the basic lineage architecture of the heart hinders research into developmental mechanisms and congenital defects4. Here, we describe the establishment of a reliable, lineage-controlled and high-throughput cardiac organoid platform. We show that cardiac mesoderm derived from human pluripotent stem cells robustly self-organises and differentiates into cardiomyocytes forming a cavity. Co-differentiation of cardiomyocytes and endothelial cells from cardiac mesoderm within these structures is required to form a separate endothelial layer. As in vivo, the epicardium engulfs these cardiac organoids, migrates into the cardiomyocyte layer and differentiates. We use this model to demonstrate that cardiac cavity formation is controlled by a mesodermal WNT-BMP signalling axis. Disruption of one of the key BMP targets in cardiac mesoderm, the transcription factor HAND1, interferes with cavity formation, which is consistent with its role in early heart tube and left chamber development5. Thus, the cardiac organoid platform represents a powerful resource for the quantitative and mechanistic analysis of early human cardiogenesis and defects that are otherwise inaccessible. Beyond understanding congenital heart disease, cardiac organoids provide a foundation for future translational research into human cardiac disorders.
2021-05-18 | PXD018306 | Pride
Project description:Notch signaling plays a role in specifying a cardiac fate but the downstream effectors remain unknown. In this study we implicate the Notch downstream effector HES5 in cardiogenesis. We show transient Hes5 expression in early mesoderm of gastrulating embryos and demonstrate, by loss and gain-of-function experiments in mouse embryonic stem cells, that HES5 favors cardiac over primitive erythroid fate. Hes5 overexpression promotes upregulation of the cardiac gene Isl1, while the hematopoietic regulator Scl is downregulated. Moreover, whereas a pulse of Hes5 instructs cardiac commitment, sustained expression after lineage specification impairs progression of differentiation to contracting cardiomyocytes. These findings establish a role for HES5 in cardiogenesis and provide insights into the early cardiac molecular network.
2017-06-22 | GSE64540 | GEO
Project description:Mamamlian cardiogenesis occurs through the development of discreate populations of first and second heart field progenitors. We have used a dual transgenic color reproter system to isolate purified populations of these progenitors. We used microarrays to detail the global programme of gene expression underlying cardiac development in mouse; All four populations of cells are derived from embryonic stem cells differentiating in vitro (day 6 of in vitro differentaition). The stem cell line has two transgenic reporters as follows:; 1. The second heart field (SHF) specific reporter of the Mef2C gene (E. Dodou, S. M. Xu, B. L. Black, Mech Dev 120, 1021 (Sep, 2003)) driving the expression of dsRed; 2. The cardiac specific enhancer ( C. L. Lien et al., Development 126, 75 (Jan, 1999)) driving the expression of eGFP. Thus, the red cells are SHF specific, the green cells are cardiac specific, and the red/green are SHF and cardiac specific. These cells are compared to the double negative cells which serve as a control. Experiment Overall Design: Embryonic stem cell derived progenitors were isolated into four distinct populations by FACS purifying these progenitors based on a two color reporter system. Four populations were then compared to each other by transcriptional profiling.
2009-09-12 | E-GEOD-17513 | biostudies-arrayexpress
Project description:Ex vivo monitored human CD34+ stem cells (SCs) injected into myocardium scar tissue have shown real benefits for the recovery of patients with myocardial infarctions. They have been used previously in clinical trials with hopeful results and are expected to be promising for cardiac regenerative medicine following severe acute myocardial infarctions. However, some debates on their potential efficacy in cardiac regenerative therapies remain to be clarified. To elucidate the levels of CD34+ SCs implication and contribution in cardiac regeneration, better identification of the main regulators, pathways, and genes involved in their potential cardiovascular differentiation and paracrine secretion needs to be determined. We first developed a protocol thought to commit human CD34+ SCs purified from cord blood toward an early cardiovascular lineage. Then, by using a microarray-based approach, we followed their gene expression during differentiation. We compared the transcriptome of undifferentiated CD34+ cells to those induced at two stages of differentiation (i.e., day 3 and day 14), with human cardiomyocyte progenitor cells (CMPCs), as well as cardiomyocytes as controls. Interestingly, in the treated cells we observed an increase in the expressions of the main regulators usually present in cardiovascular cells. We identified cell surface markers of the cardiac mesoderm, such as kinase insert domain receptor (KDR) and the cardiogenic surface receptor Frizzled 4 (FZD4), induced in the differentiated cells in comparison to undifferentiated CD34+ cells. The Wnt and TGF- pathways appeared to be involved in this activation. This study underlined the real capacity of effectively stimulated CD34+ SCs to express cardiac markers and, once induced, allowed the identification of markers that are known to be involved in vascular and early cardiogenesis, demonstrating their potential priming towards cardiovascular cells. These findings could complement their paracrine positive effects known in cell therapy for heart disease and may help improve the efficacy and safety of using ex vivo expanded CD34+ SCs.
2023-05-31 | GSE221650 | GEO
Project description:Aims: MiRNAs are post-transcriptional regulatory molecules with recognized roles in human heart development and disease. The purpose of this study was to define human miRNA expression profile in cardiac progenitors and early-differentiated cardiomyocytes and to determine if these miRNAs that are governing cardiogenesis is dependent on NKX2-5, a highly conserved pan-cardiac transcription factor. Methods: MiRNA expression profiles of pre-NKX2-5 mesoderm, cardiac progenitors and early cardiomyocytes derived from heterozygous HES3 NKX2-5eGFP/w and null NKX2-5eGFP/eGFP hESC lines were generated by small RNA sequencing in triplicates, using Illumina HiSeq. Reads between 17-28 base pairs were selected for sequence alignment to the human genome (hg19) using Bowtie2. FeatureCounts (Subread, R package) was used to count the number of reads mapping to miRNAs and analysis of statistically differentially expressed miRNA was carried out using Limma (Bioconductor) through the statistical language R. qRT–PCR validation was performed using Taqman MicroRNA Assays. Results: We identified 11 miRNAs that were differentially expressed between pre-NKX2-5 mesoderm and cardiac progenitors, and 112 differentially expressed miRNAs between cardiac progenitors and early cardiomyocytes. Four of which were validated with qRT–PCR, including canonical myogenic miRNAs such as MIR-1-1, -133A1 and 208A that were enriched in both the cardiac progenitor and early cardiomyocyte populations. Strikingly, deletion of NKX2-5 did not result in gross changes in cardiac miRNA profile either at progenitor or cardiomyocyte stage. Instead, non-hierarchical clustering and principal component analysis demonstrated that the different stages of differentiation (day 6 vs day 10) was a larger discriminator between samples than NKX2-5 genotype. Conclusion: Our study demonstrates the application of human embryonic stem cells as an in vitro model to investigate the role of miRNAs in human cardiac development. We conclude that while specific miRNAs have been identified in our study to have a role in the early stages cardiac cell fate specification, the majority of cardiac myogenic miRNA program is regulated separately from the highly conserved NKX2-5 -dependent gene network. This study provides a framework for further investigation of other key transcription factors of cardiac muscle development that might drive cardiomyogenic expression of miRNAs.
2019-11-19 | GSE134852 | GEO