The combination of valproic acid and lithium prevents hematopoietic stem/progenitor cell differentiation.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE34088 | GEO | 2011/12/15
SECONDARY ACCESSION(S): PRJNA149983
REPOSITORIES: GEO
Similar Datasets
Project description:Expression profiles of 7-day cultured HSPCs in the presence or absence of valproic acid and/or lithium. Two small molecules, valproic acid (VPA) and lithium (Li), were tested to inhibit differentiation of hematopoietic stem/progenitor (HSPC) cells in culture. HSPCs exposed to VPA and Li during differentiation-inducing culture preserved an immature cell phenotype, provided radioprotection to lethally irradiated recipients and enhanced in vivo repopulating potential. Furthermore, VPA and Li synergistically preserved expression of stem cell-related genes and repressed genes involved in differentiation. Target genes were collectively co-regulated during normal hematopoietic differentiation. Additionally, transcription factor networks were identified as possible primary regulators. Our results demonstrate that the combination of VPA and Li potently prevents differentiation at the biological and the molecular level, and provide evidence to suggest that combinatorial screening of chemical compounds may uncover possible additive/synergistic effects to modulate stem cell fate decisions. These data consist of total mRNA obtained from hematopoietic cells cultured for 7 days in the presence or absence of valproic acid and/or lithium. All samples were analyzed in independent biological triplicates.
2011-12-15 | E-GEOD-34088 | biostudies-arrayexpress
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Project description:Maintenance of the blood system requires balanced cell fate decisions by hematopoietic stem and progenitor cells (HSPCs). Because cell fate choices are executed at the individual cell level, new single-cell profiling technologies offer exciting possibilities for mapping the dynamic molecular changes underlying HSPC differentiation. Here, we have used single-cell RNA sequencing to profile more than 1600 single HSPCs, and deep sequencing has enabled detection of an average of 6558 protein-coding genes per cell. Index sorting, in combination with broad sorting gates, allowed us to retrospectively assign cells to 12 commonly sorted HSPC phenotypes while also capturing intermediate cells typically excluded by conventional gating. We further show that independently generated single-cell data sets can be projected onto the single-cell resolution expression map to directly compare data from multiple groups and to build and refine new hypotheses. Reconstruction of differentiation trajectories reveals dynamic expression changes associated with early lymphoid, erythroid, and granulocyte-macrophage differentiation. The latter two trajectories were characterized by common upregulation of cell cycle and oxidative phosphorylation transcriptional programs. By using external spike-in controls, we estimate absolute messenger RNA (mRNA) levels per cell, showing for the first time that despite a general reduction in total mRNA, a subset of genes shows higher expression levels in immature stem cells consistent with active maintenance of the stem-cell state. Finally, we report the development of an intuitive Web interface as a new community resource to permit visualization of gene expression in HSPCs at single-cell resolution for any gene of choice.
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Project description:Hematopoietic stem cells (HSCs) self-renew in bone marrow niches formed by mesenchymal progenitors and endothelial cells expressing the chemokine CXCL12, but whether a separate niche instructs multipotent progenitor (MPP) differentiation remains unclear. We show that MPPs resided in HSC niches, where they encountered lineage-instructive differentiation signals. Conditional deletion of the chemokine receptor CXCR4 in MPPs reduced differentiation into common lymphoid progenitors (CLPs), which decreased lymphopoiesis. CXCR4 was required for CLP positioning near Interleukin-7+ (IL-7) cells and for optimal IL-7 receptor signaling. IL-7+ cells expressed CXCL12 and the cytokine SCF, were mesenchymal progenitors capable of differentiation into osteoblasts and adipocytes, and comprised a minor subset of sinusoidal endothelial cells. Conditional Il7 deletion in mesenchymal progenitors reduced B-lineage committed CLPs, while conditional Cxcl12 or Scf deletion from IL-7+ cells reduced HSC and MPP numbers. Thus, HSC maintenance and multilineage differentiation are distinct cell lineage decisions that are both controlled by HSC niches.
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Project description:Post-translational modifications of core histones participate in controlling the expression of genes. Methylation of lysine 4 of histone H3 (H3K4), together with acetylation of H3K27, is closely associated with open chromatin and gene transcription. H3K4 methylation is catalyzed by KMT2 lysine methyltransferases that include the mixed-lineage leukemia 1-4 (MLL1-4) and SET1A and B enzymes. For efficient catalysis, all six require a core complex of four proteins, WDR5, RBBP5, ASH2L, and DPY30. We report that targeted disruption of Ash2l in the murine hematopoietic system results in the death of the mice due to a rapid loss of mature hematopoietic cells. However, lin-Sca1+Kit+ (LSK) cells, which are highly enriched in hematopoietic stem and multi-potent progenitor cells, accumulated in the bone marrow. The loss of Ash2l resulted in global reduction of H3K4 methylation and deregulated gene expression, including down-regulation of many mitosis-associated genes. As a consequence, LSK cells accumulated in the G2-phase of the cell cycle and were unable to proliferate and differentiate. In conclusion, Ash2l is essential for balanced gene expression and for hematopoietic stem and multi-potent progenitor cell physiology.
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Project description:The identification of small molecules which either increase the number and/or enhance the activity of CD34+ hematopoietic stem and progenitor cells (HSPCs) during ex-vivo expansion has remained challenging. Applying an unbiased in vivo chemical screen in a transgenic (c-myb:EGFP) zebrafish embryo model, histone deacetylase inhibitors (HDACI) (valproic acid, resminostat and entinostat) were shown to significantly amplify the number of phenotypic hematopoietic precursors. The identified HDACIs were confirmed to significantly enhance also the expansion of human HSPCs during ex vivo treatment. Long-term functionality of ex vivo expanded human HSPCs was verified in a xenotransplantation model using NSG mice. However, the HDACI induced proliferation of HSPCs was associated with short-term functional changes. One of the identified hits, valproic acid (VPA), increased the adhesion capacity of CD34+ cells on primary mesenchymal stromal cells and reduced their chemokine-mediated migration capacity in vitro. In line with the reduced migratory potential in vitro, homing as well as early engraftment of VPA treated human CD34+ cells was significantly impaired in the xenotransplantation model. Our data confirms that HDACI treatment leads to a net expansion of HSPCs cells with long-term engraftment potential across different species. However impaired homing and short-term-engraftment has to be kept in mind when designing clinical transplantation protocols. In addition, our gene expression analysis (RNA-Seq) revealed expression of several genes that were altered in CD34+ cells by VPA treatment including cell adhesion molecules and Notch and wnt genes which has been shown to be involved in preservation of stem cell properties.
2017-11-01 | GSE90552 | GEO
Project description:Regenerative medicine is a rapidly expanding area in research and clinical applications. Therapies involving the use of small molecule chemicals aim to simplify the creation of specific drugs for clinical applications. Adult mesenchymal stem cells have recently shown the capacity to differentiate into several cell types applicable for regenerative medicine (specifically neural cells, using chemicals). Valproic acid was an ideal candidate due to its clinical stability. It has been implicated in the induction of neural differentiation; however, the mechanism and the downstream events were not known. In this study, we showed that using valproic acid on adult mesenchymal stem cells induced neural differentiation within 24 h by upregulating the expression of suppressor of cytokine signaling 5 (SOCS5) and Fibroblast growth factor 21 (FGF21), without increasing the potential death rate of the cells. Through this, the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway is downregulated, and the mitogen-activated protein kinase (MAPK) cascade is activated. The bioinformatics analyses revealed the expression of several neuro-specific proteins as well as a range of functional and structural proteins involved in the formation and development of the neural cells.
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