A fundamental question in developmental biology is whether there are mechanisms to detect stem cells with mutations that, although not adversely affecting viability, would compromise their ability to contribute to further development. Here, we show that cell competition is a mechanism regulating the fitness of embryonic stem cells (ESCs). We find that ESCs displaying defective bone morphogenetic protein signaling or defective autophagy or that are tetraploid are eliminated at the onset of differentiation by wild-type cells. This elimination occurs in an apoptosis-dependent manner and is mediated by secreted factors. Furthermore, during this process, we find that establishment of differential c-Myc levels is critical and that c-Myc overexpression is sufficient to induce competitive behavior in ESCs. Cell competition is, therefore, a process that allows recognition and elimination of defective cells during the early stages of development and is likely to play important roles in tissue homeostasis and stem cell maintenance.
Competitive interactions eliminate unfit embryonic stem cells at the onset of differentiation.
Specimen part
View SamplesA fundamental question in developmental biology is whether there are mechanisms to detect stem cells with mutations that although do not adversely affect their viability, would compromise their ability to contribute to further development. Here we show that cell competition is a novel mechanism regulating the fitness of embryonic stem cells (ESCs). We find that ESCs displaying defective BMP signalling, defective autophagy or are tetraploid are eliminated at the onset of differentiation by wild-type cells. This elimination occurs in an apoptotic dependent manner and is mediated by secreted factors. Furthermore, during this process we find that establishment of differential cMyc levels is critical and that cMyc over-expression is sufficient to induce competitive behaviour in ESCs. Cell competition is therefore a process that allows recognition and elimination of defective cells during the early stages of development and is likely to play important roles in tissue homeostasis and stem cell maintenance.
Competitive interactions eliminate unfit embryonic stem cells at the onset of differentiation.
Specimen part
View SamplesMammalian primed pluripotent stem cells have been shown to be highly susceptible to cell death stimuli due to their low apoptotic threshold, but how this threshold is regulated remains largely unknown. Here we identify miRNA-mediated regulation as a key mechanism controlling apoptosis in the post-implantation epiblast. Moreover, we find that three miRNA families, miR-20, miR-92 and miR-302, control the mitochondrial apoptotic machinery by fine-tuning the levels of expression of the pro-apoptotic protein BIM. These families therefore represent an essential buffer needed to maintain cell survival in stem cells that are not only primed for differentiation but also for cell death.
No associated publication
Specimen part
View SamplesDeletion of Dicer by tamoxifen addition to Dicerflox/flox cells and sample collection 5 days post-deletion
No associated publication
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.
Sex
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children.
Sex, Specimen part, Disease, Disease stage
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Diagnosis of childhood tuberculosis and host RNA expression in Africa.
Disease
View SamplesGenome-wide analysis of transcriptional profiles in children <17 years of age with inflammatory diseases, bacterial or viral infections or with clinical features suggestive of infection.
Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.
Sex
View SamplesTranscriptional profiles are increasingly used to investigate the severity, subtype and pathogenesis of disease. We now describe whole blood RNA signatures and local and systemic immune mediator levels in a large cohort of adults hospitalised with influenza from which extensive clinical and investigational data was obtained. Signatures reflecting interferon-related antiviral pathways were common up to day 4 of symptoms in cases not requiring mechanical ventilatory support; in those needing mechanical ventilation, an inflammatory, activated neutrophil and cell stress/death (bacterial) pattern was seen, even early after disease onset. Identifiable bacterial co-infection was not necessary for this bacterial signature but could enhance its development while attenuating the early viral signature. Our findings emphasise the importance of timing and severity in the interpretation of transcriptomic profiles and soluble mediator levels, and identify specific patterns of immune activation that may enable the development of novel diagnostics and therapeutics
Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza.
Sex, Age, Race, Subject, Time
View SamplesThe study aimed to define transcriptional signatures for detection of active TB (TB) compared to latent TB infection (LTBI) as well as to other diseases (OD) with similar clinical phenotypes in patients with and without HIV in two African paediatric populations.
Diagnosis of childhood tuberculosis and host RNA expression in Africa.
Disease
View Samples