Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single Cell RNA-Sequencing using smart-seq2 of young and old murine hematopoietic stem cells

ABSTRACT: Ageing of the hematopoietic stem cell (HSC) compartment is characterized by skewing towards the myeloid lineage and reduced stem cell function, the molecular basis of which is largely unknown. Using single cell approaches we identify features contributing to HSC exhaustion with age. A distinct subpopulation of old HSCs carried a signature indicative of impaired stem cell function, activating p53 targets involved in senescence. In the same HSCs, we identified pro-proliferative JAK/STAT and MAPK signalling. We hypothesized that prolonged proliferation of HSCs leads to cell cycle arrest with age and therefore challenged HSCs with a constant proliferative stimulus mediated by a constitutively active form of Jak2, Jak2V617F. Indeed we observed expansion of the p53 positive population and functional impairment of the challenged HSCs. Our results reveal unexpected heterogeneity in the rate of HSC ageing and strongly implicate a role for proliferation in the p53 mediated functional decline of old HSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE87631 | GEO | 2017/05/22

SECONDARY ACCESSION(S): PRJNA345438

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Genome-wide expression analysis of self renewing hematopoietic stem cells (HSC) in control and CD70TG mice.

Project description:To study the effect of CD27 triggering on HSC biology Ageing of the hematopoietic stem cell (HSC) compartment is characterized by an accumulation of less productive HSCs with impaired lymphoid differentiation capacity, which contributes to age-dependent hematological abnormalities including anemia, myeloproliferative disorders and a decline in adaptive immunity. Since HSCs express the costimulatory receptor CD27 and because inflammation has been associated with HSC ageing, we investigated the effect of stimulation of CD27 by its inflammatory ligand CD70 on HSC maintenance. We found that CD27-triggering during CD70-driven immune activation in young mice enhances HSC self-renewal, leading to accumulation of HSCs to levels comparable with old control mice. These findings indicate that CD27-signaling accelerates HSC ageing, which is supported by the observation that CD27-triggering negatively affects HSC differentiation to the lymphoid lineage and increases myeloid differentiation. This functional change was mirrored by a corresponding difference in gene expression, as microarray analysis indicated that CD27-triggered HSCs have a strongly myeloid-biased gene signature. CD27 signaling also induced enrichment of genes associated with biological processes involved in cellular responses to DNA damage/repair and reactive oxygen species (ROS), which are associated with HSC ageing and related to increased proliferation. Therefore, we postulate that CD27 triggering during chronic inflammation contributes directly to ageing of the hematopoietic compartment.

2014-12-31 | GSE31574 | GEO

Aspp1 Preserves Hematopoietic Stem Cell Pool Integrity and Prevents Malignant Transformation

Project description:Quiescent hematopoietic stem cells (HSCs) are prone to mutagenesis, and accumulation of mutations can result in hematological malignancies. The mechanisms through which HSCs prevent such detrimental accumulation, however, are unclear. Here, we show that Aspp1 coordinates with p53 to maintain the genomic integrity of the HSC pool. Aspp1 is preferentially expressed in HSCs and restricts HSC pool size by attenuating self-renewal under steady state conditions. After genotoxic stress, Aspp1 promotes HSC cycling and induces p53-dependent apoptosis in cells with persistent DNA damage foci. Beyond these p53-dependent functions, Aspp1 attenuates HSC self-renewal and accumulation of DNA damage in p53-null HSCs. Consequently, concomitant loss of Aspp1 and p53 leads to the development of hematological malignancies, especially T-cell leukemia and lymphoma. Together, these data highlights coordination between Aspp1 and p53 in regulating HSC self-renewal and DNA damage tolerance, and suggest that HSCs possess specific mechanisms that prevent accumulation of mutations and malignant transformation. 8-week-old WT, Aspp1-/-, Mx1-Cre(+)p53flox/flox and Mx1-Cre(+)Aspp1-/-p53flox/flox mice were intraperitoneally administered with 400 μg pIpC five times every other day to obtain WT, Aspp1-/-, p53-/- and Aspp1-/-p53-/- bone marrow. 4 weeks after pIpC treatment, bone marrow lineage(-) Sca-1(+) cKit(+) cells were isolated. RNA was extracted and pooled from 3 independent mice per genotype. RNA samples were then amplified, labeled, and hybridized to independent arrays.

2015-05-20 | E-GEOD-69032 | biostudies-arrayexpress

Hematopoietic stem cells in perisinusoidal niches are protected from ageing [aged, GFP-label retaining HSCs]

Project description:With ageing, intrinsic hematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing affects also the HSC niche impairing the capacity to support HSC function is still largely unknown. Here, by using in-vivo long-term label retention assays we demonstrate that aged labelling retaining (LR) HSCs, which are in the old mice the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches and perisinusoidal Nes-GFPlow cells are uniquely preserved in shape, morphology and number upon ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches, which is linked to hematopoietic failure and decreased survival of aged mice. Overall, our data characterize for the first time the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and protect HSCs from ageing.

2019-09-02 | GSE130298 | GEO

Hematopoietic stem cells in perisinusoidal niches are protected from ageing [young and aged BM CD45-CD31+ endothelial cells]

2019-09-02 | GSE129726 | GEO

Mitochondrial Potentiation Ameliorates Age Related Heterogeneity in Hematopoietic Stem Cell Function [HSCs treated]

Project description:introduction: Ageing is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia and malignancy results: We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programmes. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs in vivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. conclusion: Our results demonstrate that MMP is a source of heterogeneity in old HSCs and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.

2020-10-19 | GSE156807 | GEO

Mitochondrial Potentiation Ameliorates Age Related Heterogeneity in Hematopoietic Stem Cell Function [MMPhigh and MMPlow HSCs]

2020-10-19 | GSE156805 | GEO

An Epigenetic Component of Hematopoietic Stem Cell Aging Amenable to Reprogramming Into a Young State

Project description:Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. While it is well established that many of the age-induced changes are intrinsic to HSCs, less is known about the stability of this state. Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations. To examine this issue at a functional level in vivo, we applied induced pluripotent stem (iPS) cell reprogramming of aged hematopoietic progenitors and allowed the resulting aged-derived iPS cells to reform hematopoiesis via blastocyst complementation. Next, we functionally characterized iPS-derived HSCs in primary chimeras and following the transplantation of 're-differentiated' HSCs into new hosts; the gold standard to assess HSC function. Our data demonstrate remarkably similar functional properties of iPS-derived and endogenous blastocyst-derived HSCs, despite the extensive chronological and proliferative age of the former. Our results therefore favor a model in which an underlying, but reversible, epigenetic component is a hallmark of HSC aging rather than being driven by an increased DNA mutation burden. Hematopoietic stem cells (HSC) have been sorted out from young and aged steady-state mice, and from recipients transplanted with young and aged bone marrow. Generated iPS and commercially available ES cells were also sorted and analyzed.

2013-03-06 | E-GEOD-44923 | biostudies-arrayexpress

Cell size is a determinant of stem cell potential during aging (HSC treatments RNA-seq dataset)

Project description:Stem cells are remarkably small in size. Human hematopoietic stem cells (HSCs) measure a mere 7 μm in diameter. Whether small size is important for stem cell function is unknown. We find that murine HSCs enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferative potential. We further show that preventing HSC enlargement by inhibiting macromolecule biosynthesis or reducing the size of large HSCs by shortening G1 averts the loss of stem cell potential. Naturally large HSCs also exhibit decreased stem cell potential indicating that large size characterizes exhausted HSCs under physiological conditions. Finally, we show that our findings are relevant to aging. A fraction of murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell function and propose that stem cell enlargement contributes to their functional decline during aging.

2021-09-19 | GSE154334 | GEO

Cell size is a determinant of stem cell potential during aging (HSC size-fractionation RNA-seq dataset)

2021-09-19 | GSE154333 | GEO

Stem cell decoupling underlies impaired lymphoid development during aging [scRNA-seq]

Project description:Mammalian aging is associated with multiple defects of hematopoiesis, most prominently with the impaired development of T and B lymphocytes. This defect is thought to originate in hematopoietic stem cells (HSCs) of the bone marrow, specifically due to the age-dependent accumulation of HSCs with preferential megakaryocytic and/or myeloid potential ("myeloid bias"). Here we tested this notion used inducible genetic labeling and tracing of HSCs in unmanipulated animals. We found that the endogenous HSC population in old mice shows reduced differentiation into all lineages including lymphoid, myeloid and megakaryocytic. Single-cell RNA sequencing and immunophenotyping (CITE-Seq) showed that HSC progeny in old animals comprised balanced lineage spectrum including lymphoid progenitors. Lineage tracing using the aging-induced HSC marker Aldh1a1 confirmed the low contribution of old HSCs across all lineages. Competitive transplantations of total bone marrow cells with genetically marked HSCs revealed that the contribution of old HSCs was reduced, but compensated by other donor cells in myeloid cells but not in lymphocytes. Thus, the HSC population in old animals becomes globally decoupled from hematopoiesis, which cannot be compensated in lymphoid lineages. We propose that this partially compensated decoupling, rather than myeloid bias, is the primary cause of the selective impairment of lymphopoiesis in the old age.

2023-04-27 | GSE229017 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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