Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA145859 | ENA |
REPOSITORIES: ENA
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Project description:Histone deacetylase (HDAC) inhibitors are widely utilized in hematopoietic malignance therapy; nevertheless, little is currently known concerning their effects on normal myelopoiesis. In order to investigate a putative interference of HDAC inhibitors in myeloid commitment of hematopoietic stem/progenitor cells (HSPCs) we treated CD34+ cells with valproic acid (VPA). Moreover, we investigate changes in gene expression induced by VPA treatment on HSPCs, by means of microarray analysis in VPA treated and untreated (CTR) CD34+ cells. VPA treatment induced H4 histone acetylation in CD34+ cells and blocked them in G0-G1 phase of cell cycle. CD34 expression is maintained for a longer time in VPA treated cells, while the physiological decrease of CD34 antigen occurred in CTR cells. Moreover, VPA favored erythrocyte and megakaryocyte differentiation at the expense of granulocyte and mono-macrophage lineages, as demonstrated by immunophenotyping, morphological and clonogenic analysis. Finally, we demonstrated that VPA up-regulated master gene regulators of erythrocyte and megakaryocyte differentiation (GFI1B and MLLT3) through histone iper-acetylation of their promoters. These results indicate that VPA treatment enhances erythrocyte and megakaryocyte differentiation at the expense of granulocyte and mono-macrophage one. Microarray data provide for the first time a detailed molecular support for the biological effects promoted by VPA treatment in HSPCs. Human CD34+ cells were purified from umbilical Cord Blood (CB) samples. After an initial 24 hours of incubation, CD34+ cells were exposed to VPA. Total cellular RNA was extracted from untreated (CTR) and VPA treated CD34+ HSCs after 48 hours of treatment.
2013-04-11 | E-GEOD-31283 | biostudies-arrayexpress
Project description:Histone deacetylase (HDAC) inhibitors are widely utilized in hematopoietic malignance therapy; nevertheless, little is currently known concerning their effects on normal myelopoiesis. In order to investigate a putative interference of HDAC inhibitors in myeloid commitment of hematopoietic stem/progenitor cells (HSPCs) we treated CD34+ cells with valproic acid (VPA). Moreover, we investigate changes in gene expression induced by VPA treatment on HSPCs, by means of microarray analysis in VPA treated and untreated (CTR) CD34+ cells. VPA treatment induced H4 histone acetylation in CD34+ cells and blocked them in G0-G1 phase of cell cycle. CD34 expression is maintained for a longer time in VPA treated cells, while the physiological decrease of CD34 antigen occurred in CTR cells. Moreover, VPA favored erythrocyte and megakaryocyte differentiation at the expense of granulocyte and mono-macrophage lineages, as demonstrated by immunophenotyping, morphological and clonogenic analysis. Finally, we demonstrated that VPA up-regulated master gene regulators of erythrocyte and megakaryocyte differentiation (GFI1B and MLLT3) through histone iper-acetylation of their promoters. These results indicate that VPA treatment enhances erythrocyte and megakaryocyte differentiation at the expense of granulocyte and mono-macrophage one. Microarray data provide for the first time a detailed molecular support for the biological effects promoted by VPA treatment in HSPCs.
2013-04-11 | GSE31283 | GEO
Project description:Analysis of the effects of valproic acid (VPA) on chronic myelogenous leukemia K562 cells. This study attempts to elucidate the effects of VPA on cell homeostasis and hematopoietic differentiation pathways in this cell line. We used ten experimental conditions comparing valproic acid-treated and untreated cells at time points 2, 6, 10, 48 and 72 hrs respectively. Experiments were performed in three biological replicates including a dye swap (represented by replicate 3, for each timepoint).
2010-12-01 | E-GEOD-19939 | biostudies-arrayexpress
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
Project description:Ex-vivo culture conditions used to expand the numbers of hematopoietic stem cells (HSCs) present within an umbilical cord blood (UCB) unit create cellular stresses leading to loss or at best maintenance of the primitive HSCs. Recently, we have shown that treatment with a histone deacetylase inhibitor, valproic acid (VPA), increases substantially the numbers of transplantable HSCs from UCB-CD34+ cells. In this report, we demonstrate that VPA treatment orchestrates cellular mechanisms that drive UCB-CD34+ cells into a primitive state in which they acquire and retain phenotypic, transcriptomic and primitive mitochondrial profiles, all of which characterize long-term HSCs. Remarkably, our data link the acquisition of the HSC phenotype to the remodeling of the mitochondrial network and p53 activation and establish both as critical regulators of ROS and therefore of HSC fate. VPA treatment leads to restructured mitochondria with reduced mass, membrane potential and ROS levels. p53 activity is critical for the activation of antioxidant defense mechanisms, which rely on magnesium superoxide dismutase (MnSOD) activity. Failure to activate the p53-MnSOD axis compromises both the acquisition and the maintenance of the HSC phenotype. These studies indicate that suppression of ROS through the coordination of p53 activity and mitochondrial remodeling determines the fate of ex-vivo expanded human HSCs
2018-10-10 | GSE110973 | GEO
Project description:Ex-vivo culture conditions used to expand the numbers of hematopoietic stem cells (HSCs) present within an umbilical cord blood (UCB) unit create cellular stresses leading to loss or at best maintenance of the primitive HSCs. Recently, we have shown that treatment with a histone deacetylase inhibitor, valproic acid (VPA), increases substantially the numbers of transplantable HSCs from UCB-CD34+ cells. In this report, we demonstrate that VPA treatment orchestrates cellular mechanisms that drive UCB-CD34+ cells into a primitive state in which they acquire and retain phenotypic, transcriptomic and primitive mitochondrial profiles, all of which characterize long-term HSCs. Remarkably, our data link the acquisition of the HSC phenotype to the remodeling of the mitochondrial network and p53 activation and establish both as critical regulators of ROS and therefore of HSC fate. VPA treatment leads to restructured mitochondria with reduced mass, membrane potential and ROS levels. p53 activity is critical for the activation of antioxidant defense mechanisms, which rely on magnesium superoxide dismutase (MnSOD) activity. Failure to activate the p53-MnSOD axis compromises both the acquisition and the maintenance of the HSC phenotype. These studies indicate that suppression of ROS through the coordination of p53 activity and mitochondrial remodeling determines the fate of ex-vivo expanded human HSCs
2018-10-10 | GSE110968 | GEO
Project description:The regenerative potential of human hematopoietic stem cells (HSCs) is well established by to their ability of life-long blood cell production and cure of a wide range of hematological diseases upon transplantation. This regenerative potential depends on HSC self-renewal and the coordinated adaptation to metabolic stress conditions. This is especially critical during ex vivo culture/manipulation of HSCs that is frequently accompanied with loss of self-renewal potential resulting in stem cell exhaustion. We have previously reported that CD34+ human hematopoietic stem and progenitor cells (HSPC) can be efficiently reprogrammed and expanded to phenotypic HSCs with long-term repopulation capacity in the presence of cytokines and valproic acid (VPA). Here, we present evidence that the SIRT1-SIRT3 axis maintains the mitochondrial activity below a critical threshold by coordinating and retaining a transcriptional and metabolic landscape of human HSCs with long-term self-renewal properties during ex vivo HSC reprogramming.
2023-04-11 | GSE218359 | GEO
Project description: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.
2012-01-24 | E-GEOD-35291 | biostudies-arrayexpress
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:Gene expression profiling of primary cord blood hematopoietic stem cell (day 0, CD34+ cells), enriched control (untreated), Scriptaid and Valproic acid expanded CD34+ cells after a week in culture. Cord blood CD34+ cells were processed individually and equal number of PC and reisolated CD34+ cells from 3-4 samples were pooled after expansion to avoid sample variations.
2014-07-29 | GSE59803 | GEO