Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Reduced lymphoid lineage priming promotes human hematopoietic stem cell expansion

ABSTRACT: Hematopoietic stem cells (HSCs) must balance self-renewal and lineage differentiation to regenerate the hematopoietic system throughout life. HSCs exhibit lineage-associated gene expression that keeps them responsive to demands of mature blood production. However, it is not known whether this process, termed lineage priming, directly influences HSC self-renewal. We investigated the link between stemness and lineage priming by attenuating the early lymphoid transcription factor E47 through ID2 over-expression (OE). Transcriptional profiling of ID2 OE HSCs showed down regulation of B-cell factors including EBF1 and FOXO1 with a concomitant increase in stemness programs and myeloerythroid factors including CEBPA and GATA1. This resulted in myeloid commitment bias from the earliest stages of differentiation. HSC self-renewal was strongly affected by this lineage perturbation resulting in an 11-fold expansion of HSCs. Thus, early lymphoid transcription factors antagonize human HSC self-renewal, providing a direct link between differentiation program priming and the maintenance of stem cell self-renewal.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45486 | GEO | 2013/12/01

SECONDARY ACCESSION(S): PRJNA194146

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Human hematopoietic stem cell expansion through modulation of lineage-associated gene expression programs

Project description:Hematopoietic stem cells (HSCs) must balance self-renewal and lineage differentiation to regenerate the hematopoietic system throughout life. HSCs exhibit lineage-associated gene expression that keeps them responsive to demands of mature blood production. However, it is not known whether this process, termed lineage priming, directly influences HSC self-renewal. We investigated the link between stemness and lineage priming by attenuating the early lymphoid transcription factor E47 through ID2 over-expression (OE). Transcriptional profiling of ID2 OE HSCs showed down regulation of B-cell factors including EBF1 and FOXO1 with a concomitant increase in stemness programs and myeloerythroid factors including CEBPA and GATA1. This resulted in myeloid commitment bias from the earliest stages of differentiation. HSC self-renewal was strongly affected by this lineage perturbation resulting in an 11-fold expansion of HSCs. Thus, early lymphoid transcription factors antagonize human HSC self-renewal, providing a direct link between differentiation program priming and the maintenance of stem cell self-renewal. Three independent lineage depleted CB samples were transduced with P-CTRL or P-ID2 and injected into 5 mice (30 mice total). From every group of 5 mice, human lin- cells were isolated and GFP+CD34+CD38-CD45RA- HSPCs were sorted by FACS.

2013-12-01 | E-GEOD-45486 | biostudies-arrayexpress

miR-125a Confers Multi-Lineage Long-Term Repopulating Stem Cell Activity to Murine and Human Hematopoietic Progenitors

Project description:Umbilical cord blood (CB) is a non-invasive, convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. One feasible option would be to expand HSCs to improve therapeutic outcome, however available protocols and the molecular mechanisms governing the self-renewal of HSC are unclear. Here we show that ectopic expression of a single miRNA, miR-125a, in purified murine and human multipotent progenitors (MPP) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and Western blot analysis, we identified a restricted set of miR-125a targets which revealed the involvement of the MAP kinase signaling pathway in conferring long-term repopulating capacity to multipotent progenitors in human and mice. Our findings offer the innovative potential to use MPP with enhanced self-renewal activity to augment limited sources of HSC to improve clinical protocols.

2017-01-11 | PXD003931 | Pride

Global Identification of the miR-130a targetome in human HSPC Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML

Project description:Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells have firmly established the existence of shared core stemness properties. However, the discordance between mRNA and protein signatures underscores an important role for post-transcriptional regulation by miRNAs in governing this critical nexus. Here, we identify miR-130a as a regulator of hematopoietic stem cell (HSC) self-renewal and lineage differentiation. Integration of mass spectrometry and chimeric AGO2 eCLIP-seq identify TBL1XR1 as a primary miR-130a target. TBL1XR1 loss of function impairs lymphoid differentiation and expands long-term (LT)-HSC. This post-transcriptional regulation by miR-130a is usurped in t(8;21) acute myeloid leukemia (AML). Reduction of miR-130a levels in t(8;21) AML cells results in altered chromatin binding and composition of the AML1-ETO complex, demonstrating that miR-130a is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Our study establishes that comprehensive identification of the miRNA targetome within primary tissue enables the discovery of novel genes and molecular networks underpinning stemness properties of normal and leukemic cells.

2024-06-22 | PXD027331 | Pride

Igf2bp2 deletion reduces energy metabolism, gIgf2bp2 deletion reduces energy metabolism, growth signaling, and aging of hematopoietic stem cells in micerowth signaling, and aging of hematopoietic stem cells in mice

Project description:Increasing evidence links metabolic activity and cell growth to decline in hematopoietic stem cell (HSC) function during aging. The Lin28b/Hmga2 pathway controls tissue development and in the hematopoietic system the postnatal downregulation of this pathway causes a decrease in self renewal of adult HSCs compared to fetal HSCs. Igf2bp2 is an RNA binding protein and a mediator of the Lin28b/Hmga2 pathway, which regulates metabolism and growth signaling by influencing RNA stability and translation of its target genes. It is currently unknown whether Lin28/Hmga2/Igf2bp2 signaling impacts on aging-associated impairments in HSC function and hematopoiesis. Here, we analyzed homozygous Igf2bp2 germline knockout mice and wildtype control animals to address this question. The study shows that Igf2bp2 deletion rescues aging phenotypes of the hematopoietic system, such as the expansion of HSC numbers in bone marrow and the biased increase of myeloid cells in peripheral blood. This rescue of hematopoietic aging coincides with reduced mitochondrial metabolism and glycolysis in Igf2bp2-/- HSCs compared to Igf2bp2+/+ HSCs. Conversely, Igf2bp2 overexpression activates protein synthesis pathways in HSCs and leads to a rapid loss of self renewal by enhancing myeloid skewed differentiation in an mTOR/PI3K-dependent manner. Together, these results show that Igf2bp2 regulates energy metabolism and growth signaling in HSCs and that the activity of this pathways influences self renewal, differentiation, and aging of HSCs.

2024-05-21 | PXD018535 | Pride

C/EBPa is required for self-renewal, lineage priming and maintenance of epigenetic configurations in hematopoietic stem cells

Project description:Transcription factors are key regulators of hematopoieticstem cells (HSCs) and act through their ability to bind DNA andimpact on gene transcription. Their functions are interpreted inthe complex landscape of chromatin but current knowledge on howthis is achieved is very limited. C/EBPa is an importanttranscriptional regulator of hematopoiesis, but its potentialfunctions in HSCs have remained elusive. Here we report that C/EBPaserves to protect adult HSCs from apoptosis and to maintain theirquiescent state. Consequently, deletion of Cebpa is associatedwith loss of self-renewal and HSC exhaustion. By combining geneexpression analysis with genome-wide assessment of C/EBPa bindingand epigenetic configurations, we show that C/EBPa acts tomodulate the epigenetic states of genes belonging to molecularpathways important for HSC function. Moreover, we demonstrate thatC/EBPa acts as a priming factor at the HSC level to activelypromote myeloid differentiation and counteract lymphoid lineagechoice. Taken together our results show that C/EBPa is a keyregulator of HSC biology, which influences the epigeneticlandscape of HSCs in order to balance different cell fate options. C/EBPaplha binding was assesed in heamatopoietic stem- and progenitor cells (LSK) and in myeloid progenitor cells (GMP) using ChIP-seq

2013-12-01 | E-GEOD-43007 | biostudies-arrayexpress

Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b) regulates the self-renewal of HSCs through the Wnt/β-catenin pathway [scRNA-Seq]

Project description:Hematopoietic stem cells (HSCs) have unique abilities to renew themselves and generate differentiated progenies of all blood cell lineages; however, how HSCs maintain the balance of self-renewal and lineage differentiation remains largely unknown. Herein, we showed that in mice the hematologic system deletion of Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b), a protein serine or threonine phosphatase highly expressed in HSCs, induces the suppression of phenotypic HSC expansion due to the blockage of cell cycle. Loss of Ppm1b impairs HSC self-renewal and hematopoietic reconstitution which were revealed by limiting dilution and BM transplantation assays. Through transcriptomic analysis, we observed that the Wnt/β-catenin pathway is downregulated in Ppm1b-deficient mice. Mechanistically, we provided evidence that Ppm1b interacted with β-catenin by performing a proximity ligation assay. Moreover, using an HN252 as a small molecule probe, we further found that Ppm1b inhibition suppressed the self-renewal of HSC and led to a decrease in common lymphoid progenitor cells, resulting in a reduction of B cells in the bone marrow and peripheral blood in turn. In the study we characterized an indispensable role of Ppm1b in regulating HSC self-renewal and B cell development via Wnt/β-catenin pathway.

2024-07-31 | GSE237746 | GEO

Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b) regulates the self-renewal of HSCs through the Wnt/β-catenin pathway [bulk RNA-Seq]

2024-07-31 | GSE237745 | GEO

The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells

Project description:Mouse haematopoietic stem cells (HSCs) undergo a post-natal transition in several properties, including a marked reduction in their self-renewal activity. We now show that the developmentally timed change in this key function of HSCs is associated with their decreased expression of Lin28b and an accompanying increase in their let-7 microRNA levels. Lentivirus(LV)-mediated overexpression of Lin28 in adult HSCs elevates their self-renewal activity in transplanted irradiated hosts, as does overexpression of Hmga2, a well-established let-7 target that is upregulated in fetal HSCs. Conversely, HSCs from fetal Hmga2-/- mice do not display the heightened self-renewal activity that is characteristic of wild-type fetal HSCs. Interestingly, overexpression of Hmga2 in adult HSCs does not mimic the ability of elevated Lin28 to activate a fetal lymphoid differentiation program. Thus Lin28b may act as a master regulator of developmentally timed changes in HSC programs with Hmga2 serving as its specific downstream modulator of HSC self-renewal potential. Lin-Sca1+cKit+ cells were isolated from E14.5 fetal livers (of wild-type of Hmga2-/- embryos) or the bone marrow of 8-12 week old mice by fluorescence activated cell sorting. The RNA was extracted and hybridized on Affymetrix mpuse gene 1.0 ST microarrays.

2013-06-27 | E-GEOD-41758 | biostudies-arrayexpress

Oncogenic Nras has a bimodal effect on hematopoietic stem cells promoting proliferation and self-renewal

Project description:Pre-leukemic mutations are thought to promote clonal expansion of hematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness. However, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative disease and leukemia. Here we show that a single allele of oncogenic NrasG12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all without immortalizing HSCs or causing leukemia in our experiments. NrasG12D also confers long-term self-renewal potential upon multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and self-renewal we assessed HSC cell cycle kinetics using H2B-GFP label retention. We found that NrasG12D had a bimodal effect on HSCs, increasing the proliferation of some HSCs while increasing the quiescence and competitiveness of other HSCs. One signal can therefore increase HSC proliferation, competitiveness, and self-renewal through a bimodal effect that promotes proliferation in some HSCs and quiescence in others. 12 RNA samples from mouse bone marrows were analyzed. There are three biological replicates for each subtype.

2014-03-14 | E-GEOD-45194 | biostudies-arrayexpress

Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type and Uhrf1-/- fetal liver hematopoietic stem cell (FL-HSCs) Transcriptomes

Project description:To investigate the molecular mechanism of Uhrf1 in controlling the self-renewal versus differentiation of FL-HSCs, high-throughput sequencing was performed to analyze the transcriptomes of WT and Uhrf1-deficient FL-HSCs.Consistent with the erythroid-biased differentiation of Uhrf1-deficient FL-HSCs, genes involved in erythrocyte differentiation were significantly enriched in Uhrf1-deficient FL-HSCs according to the Gene Ontology (GO) enrichment analysis. We generated gene signatures specific for stemness of HSCs (stem signature) or myeloerythroid progenitors (MEP signature) by subtracting the genes expressed in WT HPC(LK)s from those expressed in WT FL-HSCs or vice versa. Of the stem signature genes, 71.28% showed lower expression and 28.72% showed higher expression in Uhrf1-deficient FL-HSCs compared with WT FL-HSCs. Interestingly, among the MEP signature genes, genes enriched in erythroid differentiation (27.54%) were up-regulated in the absence of Uhrf1, whereas the remaining genes enriched in myeloid-specific genes (72.46%) were suppressed consistent with previous research. Particularly, in comparison to the WT control, Uhrf1-deficient FL-HSCs up-regulated certain erythrocyte differentiation-related genes (e.g., Gata1, Gata2, Gfi1b, Car1, Zfpm1 and Itga2b), most of which were physiologically up-regulated in HPC(LK)s, whereas some genes (Id2, Satb1, Hmga2) that play critical roles in HSC maintenance were down-regulated. These results suggested that Uhrf1 controls the self-renewal versus differentiation of FL-HSCs by suppressing the expression of the erythroid-specific genes and maintaining the expression of HSC stemness genes.

2016-11-30 | GSE85450 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data