Human and mouse embryonic stem cells (ESCs) are derived from blastocyst stage embryos but have very different biological properties, and molecular analyses suggest that the pluripotent state of human ESCs isolated so far corresponds to that of mouse derived epiblast stem cells (EpiSCs). Here we rewire the identity of conventional human ESCs into a more immature state that extensively shares defining features with pluripotent mouse ESCs. This was achieved by exogenous induction of Oct4, Klf4 and Klf2 factors combined with LIF and inhibitors of glycogen synthase kinase 3 (GSK3) and mitogen-activated protein kinase (ERK) pathway. Forskolin, a protein kinase A pathway agonist that induces Klf4 and Klf2 expression, can transiently substitute for the requirement for ectopib transgene expression. In contrast to conventional human ESCs, these epigenetically converted cells have growth properties, an X chromosome activation state (XaXa), a gene expression profile, and signaling pathway dependence that are highly similar to that of mouse ESCs. Finally, the same growth conditions allow the derivation of human induced pluripotent stem (iPS) cells with similar properties as mouse iPS cells. The generation of nave human ESCs will allow the molecular dissection of a previously undefined pluripotent state in humans, and may open up new opportunities for patient-specific, disease-relevant research.
Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs.
Specimen part
View SamplesComparison of gene expression in intestinal epithelial cells in the presence or absence of ectopic induction of MSI2 in vivo
Transformation of the intestinal epithelium by the MSI2 RNA-binding protein.
Specimen part
View SamplesTelomeres shorten with each round of cell division, and the expression of telomerase serves to lengthen telomeres. In the absence of telomerase, telomeres shorten to the point of uncapping and causes defects in tissues with high turnover, including the intestinal epithelium. In mice lacking telomerase (e.g. mTR-/-), telomeres critically shorten after several generations of telomerase deficiency, with pronounced defects in their intestine.
Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche.
Specimen part
View SamplesHematopoietic stem and progenitor cells (Lineagelo ScaI+ c-Kit+) were sorted 4 weeks post pIpC injection. RNA was extracted using TRIZOL and RNEASY RNA extraction kit. RNA was then amplified using NUGEN Pico amplification kit, fragmented and hybridized on Mouse Expression Array 430 2.0. Signal normalization was performed by RMA method. Data were analyzed using GSEA across the complete list of genes ranked by signal-to-noise ratio.
Musashi-2 controls cell fate, lineage bias, and TGF-β signaling in HSCs.
Specimen part
View SamplesLeukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Genetic and epigenetic alterations cause a dysregulated developmental program in leukemia. The MSI2 RNA binding protein has been previously shown to predict poor survival in leukemia. We demonstrate that the conditional deletion of Msi2 results in delayed leukemogenesis, reduced disease burden and a loss of LSC function. Gene expression profiling of the Msi2 ablated LSCs demonstrates a loss of the HSC/LSC and an increase in the differentiation program. The gene signature from the Msi2 deleted LSCs correlates with survival in AML patients. MSI2’s maintains the MLL self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc and Ikzf2. We further demonstrate that shRNA depletion of the MLL target gene Ikzf2 also contributes to MLL leukemia cell survival. Our data provides evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and a rationale for clinically targeting MSI2 in myeloid leukemia. Overall design: RNA-Seq was performed on sorted c-Kit high leukemic cells from 2 Msi2 -/- and 2 Msi2 f/f mice.
Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program.
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Electromagnetized gold nanoparticles mediate direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy.
Specimen part
View SamplesElectromagnetic fields (EMF) are physical energy generated by electrically charged objects that can influence numerous biologic processes, including control of cell fate and plasticity. In this study, we show that magnetic gold nanoparticles in the presence of EMF can facilitate efficient direct lineage reprogramming to induced dopamine neurons both in vitro and in vivo. Remarkably, electromagnetic stimulation leads to the specific activation of the histone acetyl transferase Brd2, resulting in H3K27 acetylation and robust activation of neuronal-specific gene expression. In vivo reprogramming in conjunction with EMF stimulation efficiently alleviated symptoms in a mouse model of Parkinsons disease (PD) in a noninvasive and controllable manner. These studies provide a proof of principle that EMF-based approaches may represent a viable and safe therapeutic strategy facilitating in vivo lineage conversion for neurodegenerative disorders.
Electromagnetized gold nanoparticles mediate direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia.
Specimen part, Cell line, Treatment
View SamplesWe demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSC), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of Msi2 in a mouse model increases HSC cell cycle progression and cooperates with BCR-ABL1 to induce an aggressive leukemia. MSI2 is over-expressed in human myeloid leukemia, and expression levels directly correlate with decreased patient survival, thereby defining MSI2 expression as a novel prognostic marker in acute myeloid leukemia (AML). Depletion of MSI2 in human myeloid leukemia cells leads to decreased proliferation and apoptosis. These data implicate the MSI2 RNA binding protein in myeloid leukemogenesis and identify a novel potential target for therapy in AML.
Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia.
Specimen part
View SamplesComparison of gene expression in intestinal epithelial cells in the presence or absence of ectopic induction of Msi1 in vivo
The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins.
Specimen part
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