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The combination of valproic acid and lithium prevents hematopoietic stem/progenitor cell differentiation.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Leonid Bystrykh

PROVIDER: E-GEOD-34088 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression profiles of 7-day cultured HSPCs in the presence or absence of valproic acid and/or lithium

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

Expression profiles of 7-day cultured HSPCs in the presence or absence of valproic acid and/or lithium

2012-01-24 | GSE35291 | GEO

Sca-1 is an early-response target of histone deacetylase inhibitors and marks hematopoietic cells with enhanced function

Project description:Expression profiles of LSK cells stimulated for 24h in the presence or in the absence of of valproic acid (VPA) The molecular process that underlies the biological effects of valproic acid (VPA), a widely used histone deacetylase inhibitor, on HSPCs was investigated by studying the early-response genes of VPA. Genome-wide gene expression studies revealed overrepresentation of genes involved in glutathione metabolism, receptor and signal transducer activity and changes in the HSPCs surface profile following short, 24h VPA treatment. Sca-1, a well-known and widely used stem cell surface marker, was identified as a prominent VPA target.VPA strongly preserved Sca-1 expression on LSK cells, but also re-activated Sca-1 on committed progenitor cells that were Sca-1 negative, thereby reverting them to the LSK phenotype. We demonstrated that re-acquired Sca-1 expression coincided with induced self-renewal capacity as measured by in vitro re-plating assays, while Sca-1 itself was not required for the biological effects of VPA as demonstrated using Sca-1 deficient progenitor cells. We show that VPA can induce several genes involved in signal transduction of which Sca-1 was shown to mark cells with increased self-renewal capacity. These data consist of total mRNA obtained from hematopoietic cells cultured for 24h in the presence or absence of valproic acid. All samples were analyzed in independent biological triplicates.

2012-09-25 | E-GEOD-41020 | biostudies-arrayexpress

mRNA profiles of four developmentally related hematopoietic cell types (LSK, L-S-K+, Gr1+ and Ter119+) isolated from the BM of B6 and D2 mice

Project description:The combination of valproic acid and lithium delays hematopoietic stem\progenitor differentiation

2012-01-25 | GSE35292 | GEO

Expression data from untreated and valproic acid (VPA) treated CD34+ Hematopoietic Stem Cells (HSCs)

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

Expression data from untreated and valproic acid (VPA) treated CD34+ Hematopoietic Stem Cells (HSCs)

2013-04-11 | GSE31283 | GEO

Sca-1 is an early-response target of histone deacetylase inhibitors and marks hematopoietic cells with enhanced function

2012-09-25 | GSE41020 | GEO

Effect of valproic acid on hematopoiesis: A functional profiling and cell phenotyping approach

2010-12-01 | GSE19939 | GEO

Effect of valproic acid on hematopoiesis: A functional profiling and cell phenotyping approach

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

In Vivo Chemical Screen Nominates Valproic Acid as Pharmacologic Modulator of Hematopoietic Stem and Progenitor Cell Activity

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

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