Gata4-dependent differentiation of c-Kit+ derived endothelial cells underlies deceptive cardiomyocyte regeneration in the heart
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE109661 | GEO | 2018/12/25
REPOSITORIES: GEO
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Project description:BACKGROUND:Although c-Kit+ adult progenitor cells were initially reported to produce new cardiomyocytes in the heart, recent genetic evidence suggests that such events are exceedingly rare. However, to determine if these rare events represent true de novo cardiomyocyte formation, we deleted the necessary cardiogenic transcription factors Gata4 and Gata6 from c-Kit-expressing cardiac progenitor cells. METHODS:Kit allele-dependent lineage tracing and fusion analysis were performed in mice following simultaneous Gata4 and Gata6 cell type-specific deletion to examine rates of putative de novo cardiomyocyte formation from c-Kit+ cells. Bone marrow transplantation experiments were used to define the contribution of Kit allele-derived hematopoietic cells versus Kit lineage-dependent cells endogenous to the heart in contributing to apparent de novo lineage-traced cardiomyocytes. A Tie2CreERT2 transgene was also used to examine the global impact of Gata4 deletion on the mature cardiac endothelial cell network, which was further evaluated with select angiogenesis assays. RESULTS:Deletion of Gata4 in Kit lineage-derived endothelial cells or in total endothelial cells using the Tie2CreERT2 transgene, but not from bone morrow cells, resulted in profound endothelial cell expansion, defective endothelial cell differentiation, leukocyte infiltration into the heart, and a dramatic increase in Kit allele-dependent lineage-traced cardiomyocytes. However, this increase in labeled cardiomyocytes was an artefact of greater leukocyte-cardiomyocyte cellular fusion because of defective endothelial cell differentiation in the absence of Gata4. CONCLUSIONS:Past identification of presumed de novo cardiomyocyte formation in the heart from c-Kit+ cells using Kit allele lineage tracing appears to be an artefact of labeled leukocyte fusion with cardiomyocytes. Deletion of Gata4 from c-Kit+ endothelial progenitor cells or adult endothelial cells negatively impacted angiogenesis and capillary network integrity.
| S-EPMC6125755 | biostudies-literature
Project description:Gata4-dependent differentiation of c-Kit+ derived endothelial cells underlies deceptive cardiomyocyte regeneration in the heart
| PRJNA431608 | ENA
Project description:Angiocrine signaling by liver sinusoidal endothelial cells (LSEC) regulates liver functions such as liver growth, metabolic maturation, and regeneration. Recently, we identified GATA4 as the master regulator of LSEC specification during development. Here, we studied endothelial GATA4 in the adult liver and in hepatic disease pathogenesis. We generated adult Clec4g-icretg/0xGata4fl/fl (Gata4LSEC KO) mice with deficiency of Gata4 in LSEC. Livers were analyzed by histology, electron microscopy, immunohistochemistry/immunofluorescence, in-situ hybridization, and by expression profiling and ATAC-sequencing of isolated LSEC. For liver regeneration, partial hepatectomy was performed. As models of liver fibrosis, CDAA diet and chronic CCl4 exposure were applied. Human single cell RNAseq data sets were analyzed for endothelial alterations in healthy and cirrhotic livers. Genetic Gata4 deficiency in LSEC in adult mice caused perisinusoidal liver fibrosis, hepatopathy and impaired liver regeneration. Sinusoidal capillarization and LSEC-to-continuous endothelial transdifferentiation were accompanied by a profibrotic angiocrine switch including de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. Increased chromatin accessibility and amplification by activated Myc mediated angiocrine PDGFB expression. In CDAA diet-induced perisinusoidal liver fibrosis, LSEC showed repression of GATA4, activation of MYC and the profibrotic angiocrine switch already detected in Gata4LSEC KO mice. Comparison of CDAA-fed Gata4LSEC KO and control mice demonstrated that endothelial Gata4 indeed protects from dietary-induced perisinusoidal liver fibrosis. In human cirrhotic livers, Gata4-positive LSEC and endothelial Gata4 target genes were reduced, while non-LSEC endothelial cells and Myc target genes including PDGFB were enriched. Endothelial GATA4 protects from perisinusoidal liver fibrosis by repressing MYC activation and profibrotic angiocrine signaling on the chromatin level. Therapies targeting the GATA4/MYC/PDGFB/PDGFRβ axis offer a promising strategy for the prevention and treatment of liver fibrosis.
2020-10-21 | GSE154824 | GEO
Project description:Angiocrine signaling by liver sinusoidal endothelial cells (LSEC) regulates liver functions such as liver growth, metabolic maturation, and regeneration. Recently, we identified GATA4 as the master regulator of LSEC specification during development. Here, we studied endothelial GATA4 in the adult liver and in hepatic disease pathogenesis. We generated adult Clec4g-icretg/0xGata4fl/fl (Gata4LSEC KO) mice with deficiency of Gata4 in LSEC. Livers were analyzed by histology, electron microscopy, immunohistochemistry/immunofluorescence, in-situ hybridization, and by expression profiling and ATAC-sequencing of isolated LSEC. For liver regeneration, partial hepatectomy was performed. As models of liver fibrosis, CDAA diet and chronic CCl4 exposure were applied. Human single cell RNAseq data sets were analyzed for endothelial alterations in healthy and cirrhotic livers. Genetic Gata4 deficiency in LSEC in adult mice caused perisinusoidal liver fibrosis, hepatopathy and impaired liver regeneration. Sinusoidal capillarization and LSEC-to-continuous endothelial transdifferentiation were accompanied by a profibrotic angiocrine switch including de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. Increased chromatin accessibility and amplification by activated Myc mediated angiocrine PDGFB expression. In CDAA diet-induced perisinusoidal liver fibrosis, LSEC showed repression of GATA4, activation of MYC and the profibrotic angiocrine switch already detected in Gata4LSEC KO mice. Comparison of CDAA-fed Gata4LSEC KO and control mice demonstrated that endothelial Gata4 indeed protects from dietary-induced perisinusoidal liver fibrosis. In human cirrhotic livers, Gata4-positive LSEC and endothelial Gata4 target genes were reduced, while non-LSEC endothelial cells and Myc target genes including PDGFB were enriched. Endothelial GATA4 protects from perisinusoidal liver fibrosis by repressing MYC activation and profibrotic angiocrine signaling on the chromatin level. Therapies targeting the GATA4/MYC/PDGFB/PDGFRβ axis offer a promising strategy for the prevention and treatment of liver fibrosis.
2020-10-21 | GSE154827 | GEO
Project description:Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions, the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in formation of portions of the atrial and ventricular septae, and generation of thin, pliable valves. The transcription factor Gata4 is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3 downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling. Keywords: genetic modification
2006-07-14 | GSE5298 | GEO
Project description:Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions, the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in formation of portions of the atrial and ventricular septae, and generation of thin, pliable valves. The transcription factor Gata4 is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3 downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling. Experiment Overall Design: To further investigate the role of Gata4 in EC development, we specifically inactivated Gata4 in endothelium and endothelium-derived cushion mesenchyme. All mice were maintained in a mixed C57BL6/129 genetic background. Gata4wt/flox; T2Cre+ mice were crossed with Gata4flox/flox mice to yield Gata4flox/flox (CONTROL); T2Cre+ (Gata4T2del) (MUTANT) mice.
2008-06-13 | E-GEOD-5298 | biostudies-arrayexpress
Project description:The Gata4 transcription factor is essential for normal heart development, but the molecular basis for its function remain poorly understood. We profiled at the whole genome level transcript changes in cardiomyocytes when Gata4 is depleted from zebrafish embryos. Our objective was to elucidate the cardiomyocyte-specific molecular program functioning downstream of Gata4 in order to better understand the role of Gata4 in cardiac morphogenesis. Six samples in total are deposited. Three replicate control samples and three replicate Gata4 morphant samples were analyzed.
2014-02-06 | E-GEOD-44233 | biostudies-arrayexpress
Project description:The second heart field (SHF) comprises a population of mesodermal progenitor cells that are added to the nascent linear heart to give rise to the majority of the right ventricle, interventricular septum, and outflow tract of mammals and birds. The zinc finger transcription factor GATA4 functions as an integral member of the cardiac transcription factor network in the SHF and its derivatives. In addition to its role in cardiac differentiation, GATA4 is also required for cardiomyocyte replication, although the transcriptional targets of GATA4 required for proliferation have not been previously identified. In the present study, we disrupted Gata4 function exclusively in the SHF and its derivatives. Gata4 SHF knockout mice die by embryonic day 13.5 and exhibit hypoplasia of the right ventricular myocardium and interventricular septum and display profound ventricular septal defects. Loss of Gata4 function in the SHF results in decreased myocyte proliferation in the right ventricle, and we identify numerous cell cycle genes that are dependent on Gata4 by microarray analysis. We show that Gata4 is required for Cyclin D2 expression in the right ventricle and that the Cyclin D2 promoter is bound and activated by GATA4 via three consensus GATA binding sites. These findings establish Cyclin D2 as a direct transcriptional target of GATA4 and support a model in which GATA4 controls cardiomyocyte proliferation by coordinately regulating numerous cell cycle genes. Keywords: genetic modification
2008-07-01 | GSE9652 | GEO
Project description:The Gata4 transcription factor is essential for normal heart development, but the molecular basis for its function remain poorly understood. We profiled at the whole genome level transcript changes in cardiomyocytes when Gata4 is depleted from zebrafish embryos. Our objective was to elucidate the cardiomyocyte-specific molecular program functioning downstream of Gata4 in order to better understand the role of Gata4 in cardiac morphogenesis.
2014-02-06 | GSE44233 | GEO
Project description:The second heart field (SHF) comprises a population of mesodermal progenitor cells that are added to the nascent linear heart to give rise to the majority of the right ventricle, interventricular septum, and outflow tract of mammals and birds. The zinc finger transcription factor GATA4 functions as an integral member of the cardiac transcription factor network in the SHF and its derivatives. In addition to its role in cardiac differentiation, GATA4 is also required for cardiomyocyte replication, although the transcriptional targets of GATA4 required for proliferation have not been previously identified. In the present study, we disrupted Gata4 function exclusively in the SHF and its derivatives. Gata4 SHF knockout mice die by embryonic day 13.5 and exhibit hypoplasia of the right ventricular myocardium and interventricular septum and display profound ventricular septal defects. Loss of Gata4 function in the SHF results in decreased myocyte proliferation in the right ventricle, and we identify numerous cell cycle genes that are dependent on Gata4 by microarray analysis. We show that Gata4 is required for Cyclin D2 expression in the right ventricle and that the Cyclin D2 promoter is bound and activated by GATA4 via three consensus GATA binding sites. These findings establish Cyclin D2 as a direct transcriptional target of GATA4 and support a model in which GATA4 controls cardiomyocyte proliferation by coordinately regulating numerous cell cycle genes. Experiment Overall Design: Onewat ANOVA with post-hoc was done with 3 genotypes with replicates. Three genetypes are Gata4flox/+; Nkx2-5+/+ (control, n=3), Gata4flox/+; Nkx2-5Cre/+ (Gata4; Nkx2-5 double heterozygous, Experiment Overall Design: 170 n=3), and Gata4flox/flox; Nkx2-5Cre/+ (Gata4 CKONkx, n=5).
2008-10-20 | E-GEOD-9652 | biostudies-arrayexpress