Expansion effect of romiplostim on hematopoietic stem and progenitor cells versus other thrombopoietin receptor agonists
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1067709 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27685928_1.fastq.gz | Fastqsanger.gz | |||
| SRR27685928_2.fastq.gz | Fastqsanger.gz | |||
| SRR27685929_1.fastq.gz | Fastqsanger.gz | |||
| SRR27685929_2.fastq.gz | Fastqsanger.gz | |||
| SRR27685930_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 20 |
Similar Datasets
Project description:Romiplostim, a thrombopoietin (TPO) receptor agonist, is a clinically approved drug that is clearly effective in reconstituting hematopoiesis in refractory aplastic anemia and idiopathic thrombocytopenic purpura. However, the mechanism underlying its biological effect is unknown, and its difference with other TPO receptor agonists remains unclear. Therefore, we determined the in vitro expansion effect of romiplostim on human CD34+ hematopoietic stem and progenitor cells (HSPCs) versus recombinant human TPO (rhTPO) and another clinically available drug eltrombopag. We also performed single-cell RNA-seq to define the effect of romiplostim on CD34+ HSPCs at the molecular level. The maximum expansion effect of romiplostim on total CD34+ cells, CD34+CD38+ progenitor cells, and CD34+CD38− immature cells was comparable to that of rhTPO, but higher than that of eltrombopag, particularly on CD34+CD38− immature cells. Single-cell RNA-seq analysis revealed that both romiplostim and eltrombopag induced signatures driven by rhTPO, but romiplostim induced molecular changes related to RHOA signaling at the most primitive subsets in HSPCs that were partially or not driven by eltrombopag. Additionally, romiplostim lacked the ability to induce TFRC expression observed by eltrombopag. In conclusion, romiplostim expands and affects human HSPCs similar to rhTPO but partially different from eltrombopag in terms of induction of gene expression.
2024-09-24 | GSE253936 | GEO
Project description:Notch1 regulates hepatic thrombopoietin production
| PRJNA1054472 | ENA
Project description:Culture of hematopoietic stem and progenitor cells in the presence of thrombopoietin induces megakaryocytic differentiation. Addition of nicotinamide to thrombopoietin-stimulated cultures results in significant increases in megkaryocytic differentiation including greater polyploidization and enhanced proplatelet formation. This study focuses on understanding the differences in the temporal gene expression pattern during differentiation with and without nicotinamide. Nicotinamide was added on day 5. Keywords: treatment response
2006-08-25 | GSE4974 | GEO
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
Project description:Goal was to detect differences in response to TLR7 versus TLR8 agonists in human monocytes from healthy donors
2014-12-24 | GSE64480 | GEO
Project description:Ten-Eleven Translocation-2 (TET2) mutations drive the expansion of mutant hematopoietic stem cells (HSCs) in clonal hematopoiesis (CH). However, the precise mechanisms by which TET2 mutations confer a competitive advantage to HSCs remain unclear. Here, through an epigenetic drug screen, we discovered that inhibition of disruptor of telomeric silencing 1-like (DOT1L), a H3K79 methyltransferase, selectively reduced the fitness of Tet2 knockout (Tet2KO) hematopoietic stem and progenitor cells (HSPCs). Mechanistically, we found that TET2 deficiency increased H3K79 dimethylation and expression of Mpl, which encodes the thrombopoietin receptor (TPO-R). Correspondingly, TET2 deficiency was associated with a higher proportion of primitive Mpl-expressing (Mpl+) cells in the HSC compartment. Importantly, inhibition of Mpl expression or the signaling downstream of TPO-R was sufficient to reduce the competitive advantage of murine and human TET2-deficient HSPCs. Our findings demonstrate a critical role for aberrant TPO-R signaling in TET2 mutation-driven CH and uncover potential therapeutic strategies against this condition.
2025-02-11 | GSE264041 | GEO
Project description:Thrombopoietin metabolically primes hematopoietic stem cells to megakaryocyte lineage differentiation
| PRJNA495332 | ENA
Project description:Single cell RNA sequencing of hematopoietic stem and progenitor cells comparing Thrombopoietin deficient and control conditions in adult and developmental stages.
2026-04-10 | GSE320303 | GEO
Project description:Umbilical cord blood (CBU) is a valuable source of hematopoietic stem cells (HSCs) due to its superior donor compatibility and lower incidence of graft-versus-host disease. However, its limited HSC content restricts its use in adult transplantation, necessitating new targets for ex vivo expansion and improved HSC potency. Mitofusin 2 (MFN2), a mitochondrial membrane fusion protein, is necessary for preserving HSC function and agonists of mitofusin activity have been characterized. We report that ex vivo culture of CBU HSCs with mitofusin agonists (MAs) enhances long-term repopulating activity by over five-fold in both primary and secondary transplantation assays without changes of total nucleated cells or phenotypic HSCs. Mechanistically, MA-treated HSCs show suppressed protein synthesis, increased autophagic flux, and elevated lysosomal acidification. Transcriptomic analysis implicates downregulation of MTOR signaling, and immunoprecipitation studies confirm a direct interaction between MFN2 and MTOR. These data support a model in which fusion-competent MFN2 sequesters MTOR, promoting a catabolic state that preserves HSC potency. Our findings suggest a novel MFN2–MTOR regulatory axis that enhances the functional expansion of human HSCs for potential therapeutic application.
2025-11-26 | GSE311386 | GEO
Project description:Hematopoietic stem cell transplantation (HSCT) is a common practice in the treatment of (malignant-) hematopoietic diseases. Umbilical Cord Blood (UCB) has become an important hematopoietic stem and progenitor cell (HSPC) source for allogeneic HSCT. However, the relatively low number of HSPCs that are present in a single UCB unit is associated with a delayed engraftment and a higher risk for graft failure. To overcome these limitations, the discovery of new therapeutics and the development of efficient ex vivo HSPC expansion conditions will help towards the successful treatment of malignant hematopoietic disease. Bone marrow derived mesenchymal stromal cells (BMSCs) are known to support the characteristic properties of HSPCs in the bone marrow microenvironment. Recently, we and others have illustrated that extracellular vesicles (EVs) have the potential to support HSPC expansion, however, the mechanism and processes responsible for the cell-cell communication of EVs are still unknown. In the current study, we investigate whether primary human BMSC EVs isolated from two different origins, fetal (fEV) and adult (aEV) tissue respectively, can increase the relative low number of HSPC found in UCB and which EV-derived components are responsible for ex vivo HSPC expansion. Interestingly, aEVs but not fEVs showed supportive ex vivo expansion capacity of UCB-HSPC. Taking advantage of the two BMSC sources with different supportive effects, we performed small RNA sequencing and proteomics analyses on the EV cargo and investigated how gene expression is modulated in HSPC after incubation with aEVs and fEVs. Proteomics analyses of the protein cargo composition of the supportive aEV versus the non-supportive fEV identified 90% of the Top100 exosome proteins present in the ExoCarta database. We identified well-defined EV markers such as ANXA1, ANXA2, ANXA5 and GAPDH as the most abundant proteins detected in both aEV and fEV. Gene Ontology (GO) analyses of the enriched proteins in aEVs and fEVs illustrated that of the proteins overrepresented in aEVs were annotated to oxidation-reduction process (eg. HADHA, HADHB), mitochondrial ATP synthesis coupled proton transport (eg. ATP5A1, ATP5B and ATP5O) or protein folding (eg. FKBP11, FKBP10, FKBP2, MESDC2). In contrast, the proteins overrepresented in fEVs were annotated to extracellular matrix organization (eg. FN1, COL12A1, COL1A1, COL6A1, CCDC80) or positive regulation of cell migration (eg. ITGA4, ITGA6, GDF15, SEMA3, APDSD6, MMP14, ICAM1, FGFR1, PDGFRA, ADAMTS1). Interestingly, we found various proteins that were overrepresented in the non-supportive fEV cargo, that are involved in transforming growth factor beta receptor (TGFBR) signaling pathway (TGFBR1, TGFBR2, TGFB1, TGFB2, LTBP1, LTBP2, BMPR1A, GDF5, GDF15, PARP1, RPS27A and COL3A1). Together this illustrates the large differences in the protein content of EV populations derived from two different origins. Small RNA sequencing identified different molecular signatures between the supportive aEVs and the non-supportive fEVs. miRNA, yRNA and piRNA were abundantly found in aEV, while fEVs contained a significant enrichment of snoRNAs. Interestingly, the microRNA cluster miR-99b/let-7e/miR-125a, previously identified to increase the number of HSPC by targeting multiple proapoptotic genes, was highly and significantly enriched in aEV in comparison to fEV. Although we identified a significant difference in EV cargo and supportive effects of aEVs and fEVs, RNAseq analyses of 24hrs treated HSPCs with aEVs or fEVs indicated that only a limited set of genes was differentially regulated when compared to cells that were only treated with cytokines. Interestingly, we identified 5 genes, (eg MTF1, PER1, HOMER1, HSPA6, ENSG00000260534) that were significantly upregulated upon aEV compared to fEV treatment of HSPC. Moreover, HSPC treated with fEVs, resulted in increased expression of genes (SKIL, SMAD7, ENG, LDLRAD4) that are involved in the negative regulation of the TGFbeta signalling pathway. Together with the TGFbeta pathway proteins that were specifically identified in the fEVs, our results suggest that HSPCs may activate a negative feedback loop upon fEV treatment that consolidate HSPC expansion. In conclusion, our study gives novel insights into the complex biological role of EVs in the bone marrow microenvironment. Systematic analyses of supportive and non-supportive human BMSC derived extracellular vesicles indicated known molecules, eg. microRNA cluster miR-99b/let-7e/miR-125a, and the presence of TGFbeta pathway components that are important regulators in the cell-cell communication via EVs and open new means for the application of EVs in the discovery of therapeutics for more efficient ex vivo HSPC expansion.
2021-02-10 | PXD022851 | Pride