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Gene expression profiling of mouse HSCs treated with Eltrombopag

ABSTRACT: Eltrombopag, a small molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy to stimulate sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. While the functional and molecular effects of Eltrombopag on megakaryopoiesis have been carefully studied in the recent past, insights into its mechanistic impact on the earliest stages of hematopoiesis have been limited. Additionally, previous studies also revealed molecular pathway of Eltrombopag apart from stimulation of TPO signaling, detail characterization remains to be addressed. In this study, we investigated the effects of Eltrombopag, in comparison with TPO, on highly-purified primary hematopoietic stem cells (HSCs) from healthy human donors. The binding of Eltrombopag to TPO-R is species-specific to human and primate cells. we also utilized HSCs isolated mouse as separation-of-function models to directly assess the molecular effect of Eltrombopag on HSCs independent of TPOR stimulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE107429 | GEO | 2018/09/17

REPOSITORIES: GEO

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Gene expression profiling of human HSCs treated with Eltrombopag

Project description:Eltrombopag, a small molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy to stimulate sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. While the functional and molecular effects of Eltrombopag on megakaryopoiesis have been carefully studied in the recent past, insights into its mechanistic impact on the earliest stages of hematopoiesis have been limited. Additionally, previous studies also revealed molecular pathway of Eltrombopag apart from stimulation of TPO signaling, detail characterization remains to be addressed. In this study, we investigated the effects of Eltrombopag, in comparison with TPO, on highly-purified primary hematopoietic stem cells (HSCs) from healthy human donors. The binding of Eltrombopag to TPO-R is species-specific to human and primate cells. we also utilized HSCs isolated mouse as separation-of-function models to directly assess the molecular effect of Eltrombopag on HSCs independent of TPOR stimulation.

2018-09-17 | GSE107428 | GEO

Human Mesenchymal Stem / Stromal Cells (hMSCs) treated with Eltrombopag show increase of the hematopoietic supporting ability

Project description:Eltrombopag (EP) is a small molecule that acts on hematopoietic cells and megakaryocytes to stimulate the hematopoiesis. Mesenchymal stem/stromal cells (MSCs) are key hematopoietic niche regulators. In the current work we aimed to assess if EP exert any effect on MSCs function, especially on their hematopoietic-supporting ability, and if so, what are the changes (including transcriptomic) induced in MSCs after EP treatment. For this purpose, MSCs were isolated from 12 healthy donors and treated with 15 uM and 50 uM of EP for 24 hours. The toxicity of the drug on MSCs and their differentiation ability were analyzed, as well as the transcriptomic profile, ROS and DNA damage and finally the changes induced in the clonogenic capacity of HSC. We observed that EP acts on MSCs decreasing their adipogenic differentiation, increasing the expression of genes involved in hypoxia and other pathways and enhancing their ability to support hematopoiesis. We used high density oligo microarrays (Affymetrix Clariom_S_Human) to obtain the global programme of gene expression underlying the effect of the Eltrombopag (EP) and Thrombopoietin (TPO) in human MSCs (derived from bone marrow) and identify the genes activity.

2023-01-07 | GSE202127 | GEO

Comparison of Human Bone Marrow CD34+ Cell Cultures Treated With TPO or Small Molecule TPO Mimetics

Project description:Small molecular TPO mimetics, LGD-4665 and eltrombopag, were efficacious in stimulating the formation of CD41+ cells from human bone marrow CD34+ cells. To better understand the mechanism of action of TPO mimetics, a microarray study was performed to compare global gene expression in CD34+ cells induced by small molecular TPO mimetics eltrombopag and LGD4665, to changes in response to recombinant human thrombopoietin (TPO). Keywords: Drug Treatment

2019-03-24 | GSE12968 | GEO

Deciphering the Differential Impact of Thrombopoietin/MPL Signaling on Hematopoietic Stem Cell Function in Bone Marrow and Spleen

Project description:Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/- and MPL-/- mice during aging. Despite severe thrombocytopenia, TPO-/- and MPL-/- mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/- and MPL-/- mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help develop novel therapeutic approaches for hematopoietic disorders.

2023-12-16 | GSE249912 | GEO

Blood transcriptome and clonal T cell correlates of response and nonresponse to eltrombopag therapy in a cohort of patients with chronic immune thrombocytopenia

Project description:We evaluated the longitudinal effect of eltrombopag, a thrombopoietin receptor agonist, on gene expression in heavily pretreated patients with chronic immune thrombocytopenia (ITP) using blood transcriptome analysis on pretreatment, and following 1 week and 1 month of treatment samples. A strong stimulation of 208 eltrombopag-induced genes was identified in responders at 1-week time point. 90% of these genes are present in platelets, with GATA1, THPO, VIPAS39 and TGFB1 as top upstream regulators. Subsequently, despite a continued increase in platelet in responders, the eltrombopag-induced gene expression decreased at 1 month compared with the level at 1-week time point. This novel observation of the longitudinal effect of eltrombopag therapy over time suggests different stages of eltrombopag response. Non-responders did not exhibit eltrombopag-induced gene expression changes. This study provides novel insights into the mechanisms of eltrombopag response and nonresponse.

2021-03-21 | GSE112278 | GEO

Transcription profiling by array of mouse wild type, or mutant or knocked out for Myb, p300 or Mpl bone marrow lineage- Sca-1+ c-Kit+ cells

Project description:Thrombopoietin (TPO), acting through its receptor Mpl, has two major physiological roles: ensuring production of sufficient platelets via stimulation of megakaryocyte production, and maintaining hematopoietic stem cell (HSC) quiescence. Mpl also controls circulating TPO concentration via receptor-mediated internalisation and degradation. We demonstrate that the megakaryocytosis and increased platelet mass in mice with mutations in the Myb or p300 genes causes reduced circulating TPO concentration and TPO starvation of the stem cell compartment, which is exacerbated because these cells additionally exhibit impaired responsiveness to TPO. Total RNA obtained from bone marrow Lineage- Sca-1+ c-Kit+ cells of mice that were mutant or knocked out for Myb, p300 or Mpl were compared to wild type samples. We have found that HSCs from MybPlt4/Plt4 and p300Plt6/Plt6 mice show altered expression of TPO-responsive genes, suggesting that TPO starvation is an important factor in the hematopoietic phenotypes observed in these mice .

2011-01-31 | E-TABM-1050 | biostudies-arrayexpress

Early gene expression in mouse hematopoietic stem cells induced by Thrombopoietin stimulation and irradiation

Project description:Thrombopoietin (TPO) was shown to prevent irradaition-induced hematopoietic stem cells (HSCs) loss of function. A single injection of TPO to mice 45-60 min prior to irradiation is sufficient to reverse the long-lasting accumulation of persistent DNA damage. We used microarrays to analyze whether this effet can relie on TPO-induced specific transcriptional changes during this early time.

2017-12-31 | GSE84195 | GEO

Transcription profiling by array of mouse bone marrow lineage- c-Kit+ Sca-1+ cells in which floxed Mpl alleles were specifically and homozygously deleted in megakaryocytes and platelets

Project description:Thrombopoietin (TPO) acting via its receptor Mpl is the major cytokine regulator of platelet number. To precisely define the role of specific hematopoietic cells in TPO dependent hematopoiesis, we generated mice that express the Mpl receptor normally on stem/progenitor cells but lack expression on megakaryocytes and platelets (MplPF4cre/PF4cre). MplPF4cre/PF4cre mice displayed profound megakaryocytosis and thrombocytosis with a remarkable expansion of megakaryocyte-committed and multipotential progenitor cells, the latter displaying biological responses and a gene expression signature indicative of chronic TPO over-stimulation as the underlying causative mechanism, despite a normal circulating TPO level. Thus, TPO signaling in megakaryocytes is dispensable for platelet production; its key role in control of platelet number is via generation and stimulation of the bipotential megakaryocyte precursors. Nevertheless, Mpl expression on megakaryocytes and platelets is essential to prevent megakaryocytosis and myeloproliferation by restricting the amount of TPO available to stimulate the production of megakaryocytes from the progenitor cell pool.

2014-06-10 | E-MTAB-2389 | biostudies-arrayexpress

Identification of differentially expressed genes upon treatment with Eltrombopag in HL60 cells

Project description:Identification of differentially expressed genes upon treatment with Eltrombopag in HL60 cells. HL60 cells were untreated, or treated with 3ug/ml of Eltrombopag for 36 hrs in RPMI with 10% FBS HL60 cells were untreated, or treated with 3ug/ml of Eltrombopag for 36 hrs in RPMI with 10% FBS

2012-06-24 | E-GEOD-37580 | biostudies-arrayexpress