Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Adhesion GPCR, latrophilin-2, specifies cardiac lineage commitment through CDK5, Src, and P38MAPK

ABSTRACT: Identifying lineage-specific markers is pivotal for understanding developmental processes and developing cell therapies. Here, we report a new cardiomyogenic cell surface marker latrophilin-2 (Lphn2), an adhesion G protein-coupled receptor. When mouse and human pluripotent stem cells (PSCs) were stimulated with BMP4, Activin A, and bFGF, they differentiated into cardiac lineage cells. Lphn2 was selectively expressed on cardiac progenitor cells (CPCs) and cardiomyocytes (CMCs) during the differentiation of mouse PSCs, and cell sorting with an anti-Lphn2 antibody promoted the isolation of populations highly enriched in CPCs and CMCs. Lphn2 knock-down or knock-out PSCs did not express cardiac genes. To investigate the molecular mechanism underlying the induction of cardiac differentiation by Lphn2, we used the Phospho Explorer Antibody Array, which encompasses nearly all known signaling pathways. Lphn2-dependent phosphorylation was strongest for cyclin-dependent kinase 5 (CDK5) at Tyr15. We identified CDK5, Src, and P38MAPK as key downstream molecules of Lphn2. These findings provide a valuable tool for isolating cardiomyogenic progenitors and CMCs from PSCs and shed light on the still-unknown mechanisms of cardiac differentiation.

ORGANISM(S): Mus musculus Rattus norvegicus Homo sapiens

PROVIDER: GSE92923 | GEO | 2017/01/06

SECONDARY ACCESSION(S): PRJNA358870

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Identification of Latrophilin-2, a Specific Cell-surface Marker for Cardiac Progenitor Cells, and its Functional Significance in Heart Development [RNA-Seq]

Project description:Background: Identification of a lineage-specific marker plays a pivotal role in understanding developmental process and is necessary to isolate a certain cell type with high purity for therapeutic purposes. Here, we report a new cardiac-specific marker and demonstrate its functional significance in cardiac development. Methods: When mouse pluripotent stem cells (PSCs) were stimulated with BMP4, Activin A, and bFGF, they differentiated into cardiac cells. To screen molecules expressed on cardiac progenitor cell (CPC) surfaces compared to those on undifferentiated PSCs, we isolated Flk1+/PdgfRa+ cells at differentiation day 4 and performed microarray analysis. Results: Among candidates, we identified a new G protein-coupled receptor, latrophilin-2 (Lphn2). Here, we report this new cardiac-specific surface marker, Lphn2, expressed specifically on CPCs and cardiomyocytes (CMCs) during mouse and human PSC differentiation in vitro and exclusively in the heart during mouse embryonic development. Lphn2 knockout in mice was embryonically lethal because of severe heart, but not vascular, defects. PSC-derived Lphn2+ cells, but not Lphn2- cells, differentiated into CMCs and regenerated the myocardium when transplanted into infarcted hearts. Transplanted Lphn2+ cells improved left ventricular systolic function and reduced infarct sizes. Analysis of the signaling pathway indicated that cyclin-dependent kinase 5 is downstream of Lphn2 and collaborates with Src kinase to induce P38MAP kinase phosphorylation, subsequently activating cardiac-related gene transcription. Conclusion: Lphn2 is a functionally significant cell-surface marker for cardiac progenitor and cardiomyocytes. These findings provide a valuable tool for isolating cardiomyogenic progenitors and CMCs from PSCs and shed light on heart development and regeneration.

2018-12-31 | GSE102973 | GEO

Lysophosphatidic Acid Receptor 4 is transiently expressed during cardiac differentiation and critical for repair of the damaged heart

Project description:Efficient differentiation of pluripotent stem cells (PSCs) into cardiac cells is essential for the development of new therapeutic modalities to repair damaged heart tissue. We identified a novel cell surface marker, the G protein-coupled receptor lysophosphatidic acid receptor 4 (LPAR4), specific to cardiac progenitor cells (CPCs) and determined its functional significance and therapeutic potential. During in vitro differentiation of mouse and human PSCs toward cardiac lineage, LPAR4 expression peaked after 3−7 days of differentiation in cardiac progenitors and then declined. In vivo, LPAR4 was specifically expressed in the early stage of embryonal heart development, and as development progressed, LPAR4 expression decreased and was non-specifically distributed. We identified the effective agonist octadecenyl phosphate and a p38 MAPK blocker, as the downstream signal blocker. Sequential stimulation and inhibition of LPAR4 using these agents enhanced the in vitro efficiency of cardiac differentiation from mouse and human PSCs. Importantly, in vivo, this sequential stimulation and inhibition of LPAR4 reduced the infarct size and rescued heart dysfunction in mice. In conclusion, LPAR4 is a novel CPC marker transiently expressed only in heart during embryo development. Modulation of LPAR4-positive cells may be a promising strategy for repairing myocardium after myocardial infarction.

2016-06-17 | GSE83434 | GEO

Mus musculus

Project description:Adhesion GPCR, latrophilin-2, specifies cardiac lineage commitment through CDK5, Src, and P38MAPK

| PRJNA358870 | ENA

A Regulatory Pathway Involving Notch1/β-Catenin/Isl1 Determines Cardiac Progenitor Cell Fate

Project description:The regulation of multipotent cardiac progenitor cell (CPC) expansion and subsequent differentiation into cardiomyocytes, smooth muscle, or endothelial cells is a fundamental aspect of basic cardiovascular biology and cardiac regenerative medicine. However, the mechanisms governing these decisions remain unclear. Here, we show that Wnt/β-Catenin signaling, which promotes expansion of CPCs, is negatively regulated by Notch1-mediated control of phosphorylated β-Catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and β-Catenin negatively, regulated expression of the cardiac transcription factors, Isl1, Myocd and Smyd1. Surprisingly, disruption of Isl1, normally expressed transiently in CPCs prior to their differentiation, resulted in expansion of CPCs in vivo and in an embryonic stem (ES) cell system. Furthermore, Isl1 was required for CPC differentiation into cardiomyocyte and smooth muscle cells, but not endothelial cells. These findings reveal a regulatory network controlling CPC expansion and cell fate that involve unanticipated functions of β-Catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs. YFP+ cells marking precardiac mesoderm (Isl1-cre domain) were FACS-sorted (w/wo stabilized Beta-catenin). Their total RNA was amplified with the WT-Ovation Pico RNA Amplification System, fragmented and labeled with the FL-Ovation cDNA Biotin Module V2 (Nugen). The hybridization, staining and scanning of the Affymetrix GeneChips were performed in the Gladstone Genomics Core Lab. Raw data generated from at least three independent experiments were further analyzed by the group of Dr. Ru-Fang Yeh at the Center for Informatics and Molecular Biostatistics, UCSF.

2009-05-13 | E-GEOD-15232 | biostudies-arrayexpress

A Regulatory Pathway Involving Notch1/β-Catenin/Isl1 Determines Cardiac Progenitor Cell Fate

2009-05-13 | GSE15232 | GEO

Essential and unexpected role of YY1 to promote mesodermal cardiac differentiation

Project description:Rationale: Cardiogenesis is regulated by a complex interplay between transcription factors and chromatin-modifying enzymes. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). Objective: To identify novel regulators of mesodermal cardiac lineage commitment. Methods and Results: We performed a bioinformatic-based transcription factor-binding site analysis on upstream promoter regions of genes that are enriched in ES cell-derived CPCs. From 32 candidate transcription factors screened, we found that YY1, a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1 kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays and in vivo chromatin immunoprecipitation (ChIP) and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with GATA4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by ES cell-based assays where we show that the over-expression of YY1 enhanced the cardiogenic differentiation ES cells into CPCs in a cell autonomous manner. Conclusion: These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes. We report the identification of putative YY1 target genes in cardiac progenitor cells (CPCs). Two samples of independently FACS-purified eGFP+ CPCs were examined against the input.

2013-06-01 | E-GEOD-35370 | biostudies-arrayexpress

Fms-like tyrosine kinase 3 (Flt3) contributes to a receptor tyrosine kinase signature regulating the cardiac side population

Project description:Fms-like tyrosine kinase 3 (Flt3) is a regulator of hematopoietic progenitor cells. It is a target of tyrosine kinase inhibitors (TKIs) used for acute myeloid leukemia treatment. Flt3 and its ligand (Flt3L) are expressed in the heart and cardiac side effects occur under Flt3-targeting TKIs. Whether Flt3/Flt3L also regulate cardiac progenitor cells (CPCs), however, is not known. The cardiac side population (SP) is a pool of heterogenous CPCs that can give rise to all cardiac lineages, hence contributing to cardiovascular homeostasis. Here we show that SP-CPCs produce and are responsive to Flt3L. Compared to wild-type, SP-CPCs from flt3L-/- mice are less abundant, with less contribution of CD45-CD34+ cells, and lower expression of gene sets related to epithelial-to-mesenchymal transition, cardiovascular development and stem cell differentiation. Upon culturing and compared to wild-type, flt3L-/- Sca1+CD31- SP-CPCs show increased proliferation and less vasculogenic commitment, but differentiation can be induced in the presence of receptor tyrosine kinase-activating growth factors. The observed differences are associated with decreased microvascularisation and global systolic function of flt3L-/- hearts. Thus, Flt3 contributes to a receptor tyrosine kinase signature necessary for the maintenance and functionality of SP-CPCs. These findings have potential implications regarding cardiovascular side effects observed under TKI therapy.

2021-11-30 | GSE168207 | GEO

Cardiac differentiation of embryonic stem cells recapitulates embryonic cardiac development.

Project description:Mouse embryonic stem cells can differentiate in vitro into spontaneously contracting cardiomyocytes. The main objective of this study was to investigate cardiogenesis in cultures of differentiating embryonic stem cells (ESCs) and to determine how closely it mimics in vivo cardiac development. We identified and isolated a population of cardiac progenitor cells (CPCs) through the use of a reporter DNA construct that allowed the expression of a selectable marker under the control of the Nkx2.5 enhancer. We proceeded to characterize these CPCs by examining their capacity to differentiate into cardiomyocytes and to proliferate. We then performed a large-scale temporal microarray expression analysis in order to identify genes that are uniquely upregulated or downregulated in the CPC population. We determined that the transcriptional profile of the mESC derived CPCs was consistent with pathways known to be active during embryonic cardiac development. We conclude that in vitro differentiation of mESCs recapitulates the early steps of mouse cardiac development. Keywords: embryonic stem cell, differentiation, cardiac progenitor, cardiogenesis

2007-08-30 | GSE5671 | GEO

Transcriptional profiling by array of human cardiac progenitors and cardiomyocytes generated from embryonic bodies, directed differentiation of hESCs with PDGFa or co-culturing hESCs with END2 cell line.

Project description:Human cardiomyocytes can be generated from human embryonic stem cells (hESCs) in vitro by a variety of methods, including co-culture with visceral endoderm-like cell lines and growth factor directed differentiation as monolayers or three-dimensional embryonic bodies. To enable the identification, purification and characterisation of human embryonic stem cell derived cardiomyocytes (CMs) and cardiac progenitor cells (CPCs), we introduced sequences encoding GFP into the NKX2-5 locus by homologous recombination. We found that NKX2-5GFP hESCs facilitate quantification of cardiac differentiation, purification of hESC-derived committed cardiac progenitor cells and cardiomyocytes and the standardization of differentiation protocols.

2011-11-16 | E-MEXP-3371 | biostudies-arrayexpress

Chromatin accessibility profiles of early cardiac precursor cells at single cell resolution

Project description:Transcriptional networks governing cardiac precursor cell (CPC) specification are incompletely understood due in part to limitations in distinguishing CPCs from non-cardiac mesoderm in early gastrulation. We leveraged detection of early cardiac lineage transgenes within a granular single cell transcriptomic time course of mouse embryos to identify emerging CPCs and describe their transcriptional profiles. Mesp1, a transiently-expressed mesodermal transcription factor (TF), is canonically described as an early regulator of cardiac specification. However, we observed perdurance of CPC transgene-expressing cells in Mesp1 mutants, albeit mis-localized, prompting us to investigate the scope of Mesp1’s role in CPC emergence and differentiation. Mesp1 mutant CPCs failed to robustly activate markers of cardiomyocyte maturity and critical cardiac TFs, yet they exhibited transcriptional profiles resembling cardiac mesoderm progressing towards cardiomyocyte fates. Single cell chromatin accessibility analysis defined a Mesp1-dependent developmental breakpoint in cardiac lineage progression at a shift from mesendoderm transcriptional networks to those necessary for cardiac patterning and morphogenesis. These results reveal Mesp1-independent aspects of early CPC specification and underscore a Mesp1-dependent regulatory landscape required for progression through cardiogenesis.

2023-04-07 | GSE210638 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data