Thrombopoietin metabolically primes hematopoietic stem cells to megakaryocyte lineage differentiation
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PROVIDER: PRJNA495332 | ENA |
REPOSITORIES: ENA
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Project description:During acute myelosuppression or thrombocytopenia, bone marrow (BM) hematopoietic cells respond rapidly to replenish peripheral blood platelets. While the cytokine Thrombopoietin (Thpo) concomitantly regulates platelet production and maintains HSC stem cell potential whether Thpo directly controls Mk-lineage differentiation of HSCs is unclear. Stress hematopoiesis requires quiescent HSCs to proliferate, a process which depends on a higher energy production. However, whether this switch of metabolic state relates to lineage differentiation of HSCs is not known. We here show that Thpo rapidly upregulates mitochondrial activity in HSCs which was accompanied by preferential differentiation to Mk-lineage. During unperturbed hematopoiesis, HSCs with high mitochondrial content and activity exhibit Mk-lineage biased differentiation. Furthermore, Thpo rapidly skewed HSCs to express a tetraspanin molecule, CD9, which expression correlated to mitochondria cell content. While highly proliferative, mitochondrial-rich HSCs were resistant to apoptosis and oxidative stress upon Thpo stimulation. Thpo regulated mitochondrial activity did not associate with high levels of cMpl expression but was influenced by non-nuclear mitochondrial translocation of phosphorylated of STAT3 at serine 727. Our data reveals that HSCs are metabolically heterogeneous and higher mitochondrial activity primes HSCs toward the Mk lineage differentiation. We also uncover a pivotal role of Thpo in regulating the rapid Mk-lineage commitment during stress hematopoiesis. Our findings suggest that mitochondria metabolism primes HSCs not only to exit dormancy but toward direct differentiation to Mk lineage.
2018-12-31 | GSE121001 | GEO
Project description:Gene expression profile of primary human CD34+/CD38lo cells differentiating along the megakaryocyte lineage.
2004-01-15 | E-MEXP-70 | biostudies-arrayexpress
Project description:We newly identified prospectively-isolatable unipotent megakaryocyte progenitor population (MegP) as the major source of megakaryocytes, which emerges directly from early stage of hematopoiesis bypassing megakaryocyte-erythroid lineage bifurcation and contributes to physiological and pathological human megakaryopoiesis. To explore gene expression signature of hematopoietic stem/progenitor populrations miroarry-based whole transcriptome analysis was performed. As a result, gene expression signature of MegP clearly reflected its differentiation potential.
2016-02-02 | GSE77439 | GEO
Project description:Infections are associated with extensive consumption of blood platelets representing a high risk for health. How the hematopoietic system coordinates the rapid and efficient regeneration of this particular lineage during such stress scenarios remains unclear. Here we report that the phenotypic hematopoietic stem cell (HSC) compartment contains highly potent megakaryocyte-committed progenitors (hipMkPs), a cell population that shares many features with multipotent HSCs and serves as a lineage-restricted emergency pool for inflammatory insults. Our data show that during homeostasis, hipMkPs are maintained in a primed but quiescent state, thus contributing little to steady-state megakaryopoiesis. Moreover, homeostatic hipMkPs show expression of megakaryocyte lineage priming transcripts for which protein synthesis is suppressed. We demonstrate that acute inflammatory signaling instructs activation of hipMkPs, as well as Mk protein production from pre-existing transcripts and drives a rapid maturation of hipMkPs and other Mk progenitors. This results in an efficient regeneration of platelets that are lost during inflammatory insult. Thus, our study reveals an elegant emergency machinery that counteracts life-threating depletions in the platelet pool during acute inflammation.
2015-08-26 | PXD001500 | Pride
Project description:Background: Recent advances in single-cell techniques have provided the opportunity to finely dissect cellular heterogeneity within populations previously defined by âbulkâ assays and to uncover rare cell types. In human hematopoiesis, megakaryocytes and erythroid cells differentiate from a shared precursor, the megakaryocyte-erythroid progenitor (MEP), which remains poorly defined.Results: To clarify the cellular pathway in erythro-megakaryocyte differentiation, we correlated the surface immunophenotype, transcriptional profile and differentiation potential of individual MEP cells. Highly purified, single MEP cells (n=681) were analyzed using index fluorescence-activated cell sorting with parallel targeted transcriptional profiling of the same cells performed using a specifically designed panel of 87 genes. Differentiation potential was tested in novel, single-cell differentiation assays. Our results demonstrated that immunophenotypic MEP in fact comprise three distinct subpopulations: (1) âPre-MEPâ, enriched for erythroid/megakaryocyte progenitors but with residual myeloid differentiation capacity (2) âE-MEPâ, strongly biased towards erythroid differentiation, and (3) âMK-MEPâ, a previously undescribed, rare population of cells that are bipotent but primarily generate megakaryocytic progeny. Therefore, conventionally-defined MEP are in fact a mixed population: a minority give rise to mixed-lineage colonies while the majority of cells are transcriptionally-primed to generate exclusively single-lineage output. Conclusions: Our study clarifies the cellular hierarchy in human megakaryocyte/erythroid lineage commitment and highlights the importance of using a combination of single-cell approaches to dissect cellular heterogeneity and identify rare cell types within a population. We present a novel immunophenotyping strategy that enables the prospective identification of specific intermediate progenitor populations in erythro-megakaryopoiesis, allowing for in-depth study of disorders including inherited cytopenias, myeloproliferative disorders and erythromegakaryocytic leukemias. Multiplex RT-PCR gene expression profiling of 807 human megakaryocyte-erythroid progenitor cells (MEP) isolated from three healthy donors by apheresis following G-CSF treatment. Cells were excluded if more than 70 assays did not result in amplification or displayed Ct higer than 13 for B2M or higher than 15 for GAPDH. Furthermore cells with a mean non-dropout Ct value greater than 20 were removed. This resulted in a dataset of 681 cells, which were subsequently normalised to the mean of B2M and GAPDH expression.
2016-04-02 | E-GEOD-79331 | biostudies-arrayexpress
Project description:Loss of PRC2 subunits primes lineage choice during exit of pluripotency
| PRJNA646712 | ENA
Project description:To clarigy the molecular mechanism underlying the IMiD-induced megakaryocytic lineage commitment in human megakaryocyte/erythrocyte progenitors, we performed transcriptome analysis of CD41-CD105+ and CD41+CD105- cells obtained from megakaryocyte/erythrocyte progenitors treated with lenalidomide for 72 hours. Differentially expressed genes were comprehensively evaluated by gene set enrichment analysis. CD105-CD41+ cells showed the enrichment in the expression of genes related to megakaryocytes and platelet, whereas genes related to erythroid lineage were negatively enriched. CD41+CD105- cells expressed higher levels of transcription factors required for megakaryocyte differentiation including FLI1, RUNX1, and MEIS1. Furthermore, we performed a knockdown strategy with small interfering RNA against MEIS1 mRNA, confirming that lenalidomide-induced megakaryocyte commitment should be due to the up-regulation of MEIS1 in megakaryocyte/erythrocyte progenitors.
2021-11-25 | GSE162212 | GEO
Project description:This collection contains microRNA expression profiling data for samples purified from umbilical cord blood, belonging to one of the followiing populations: MEP, MEGA1, MEGA2, ERY1, ERY2, ERY3. MEP: megakaryocyte-erythrocyte precursors (defined by CD34+ CD38+ IL-3Ra- CD45RA- ); MEGA1: megakaryocyte population 1 (defined by CD34+ CD61+ CD41+ CD45- ); MEGA2: megakaryocyte population 2 (defined by CD34- CD61+ CD41+ CD45- ); ERY1: erythrocyte population 1 (defined by CD34+ CD71+ GlyA- ); ERY2: erythrocyte population 2 (defined by CD34- CD71+ GlyA- ); ERY3: erythrocyte population 3 (defined by CD34- CD71+ GlyA+ ). Keywords: microRNA, miRNA, MEP, megakaryocyte, erythrocyte, lineage specification
2008-06-10 | GSE10593 | GEO
Project description:MicroRNAs are small non-coding RNAs that regulate cellular development by interfering with mRNA stability and translation. We defined the kinetics of global microRNA expression during the differentiation of murine hematopoietic progenitors into megakaryocytes. Of 435 miRNAs analyzed, 13 were upregulated and 81 were downregulated. Many of these changes are consistent with miRNA profiling studies of human megakaryocytes and platelets, although new patterns also emerged. Among 7 conserved miRNAs that were upregulated most strongly in megakaryocytes, 6 were also induced in the related erythroid lineage. MiR-146a was strongly upregulated during mouse and human megakaryopoiesis, but not erythropoiesis. However, overexpression of miR-146a in mouse bone marrow hematopoietic progenitor populations produced no detectable alterations in megakaryocyte development or platelet production in vivo or in colony assays. Our findings extend the repertoire of differentially regulated miRNAs during murine megakaryopoiesis and provide a useful new dataset for hematopoiesis research. In addition, we show that enforced hematopoietic expression of miR-146a has minimal effects on megakaryopoiesis. These results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibits megakaryopoiesis cell-autonomously. Exiqon locked nucleic acid (LNA) microarrays were used to compare microRNA expression in starting populations (ter 119- progenitors) and purified megakaryocytes. Day13.5-14.5 murine fetal livers (strain CD1) were depleted of erythroid cells and cultured with thrombopoietin to generate megakaryocytes. Each total RNA sample (0.5 μg per reaction) was labeled with Hy3 and Hy5 dyes using the Exiqon Power Labeling Kit and automated microarray hybridizations and washes were performed on a Tecan HS4800 station with 20 hr hybridization at 56ºC. Dye-swap pairs of three replicate experiments comparing Ter119- fetal liver cells vs. BSA-purified megakaryocytes were co-hybridized to six arrays. The geometric average of the 532 and 635 measurements after normalization was determined for each sample.
2010-12-07 | E-GEOD-22480 | biostudies-arrayexpress
Project description:Background: Recent advances in single-cell techniques have provided the opportunity to finely dissect cellular heterogeneity within populations previously defined by “bulk” assays and to uncover rare cell types. In human hematopoiesis, megakaryocytes and erythroid cells differentiate from a shared precursor, the megakaryocyte-erythroid progenitor (MEP), which remains poorly defined.Results: To clarify the cellular pathway in erythro-megakaryocyte differentiation, we correlated the surface immunophenotype, transcriptional profile and differentiation potential of individual MEP cells. Highly purified, single MEP cells (n=681) were analyzed using index fluorescence-activated cell sorting with parallel targeted transcriptional profiling of the same cells performed using a specifically designed panel of 87 genes. Differentiation potential was tested in novel, single-cell differentiation assays. Our results demonstrated that immunophenotypic MEP in fact comprise three distinct subpopulations: (1) “Pre-MEP”, enriched for erythroid/megakaryocyte progenitors but with residual myeloid differentiation capacity (2) “E-MEP”, strongly biased towards erythroid differentiation, and (3) “MK-MEP”, a previously undescribed, rare population of cells that are bipotent but primarily generate megakaryocytic progeny. Therefore, conventionally-defined MEP are in fact a mixed population: a minority give rise to mixed-lineage colonies while the majority of cells are transcriptionally-primed to generate exclusively single-lineage output. Conclusions: Our study clarifies the cellular hierarchy in human megakaryocyte/erythroid lineage commitment and highlights the importance of using a combination of single-cell approaches to dissect cellular heterogeneity and identify rare cell types within a population. We present a novel immunophenotyping strategy that enables the prospective identification of specific intermediate progenitor populations in erythro-megakaryopoiesis, allowing for in-depth study of disorders including inherited cytopenias, myeloproliferative disorders and erythromegakaryocytic leukemias.
2016-04-02 | GSE79331 | GEO