Differences in cell cycle status underlie transcriptional heterogeneity in the HSC compartment
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ABSTRACT:
PROVIDER: PRJNA422622 | ENA |
REPOSITORIES: ENA
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Project description:Hematopoietic stem cells (HSCs) are considered a heterogeneous cell population. In an attempt to further resolve the HSC compartment, we characterized a retinoic acid (RA) reporter mouse line. Sub-fractionation of the HSC compartment in RA-CFP reporter mice demonstrated that RA-CFP-dim HSCs were largely non-proliferative and displayed superior engraftment potential in comparison to RA-CFP-bright HSCs. Gene expression analysis demonstrated higher expression of RA-target genes in RA-CFP-dim HSCs, contrasting the RA-CFP reporter expression, but both RA-CFP-dim and –bright HSCs responded efficiently to ATRA in vitro. Single-cell RNA-sequencing of >1,200 HSCs showed that differences in cell cycle activity constitutedthe main driver of transcriptional heterogeneity in HSCs. Moreover, further analysis of the single-cell RNA-seq data revealed that stochastic low-level expression of distinct lineage-affiliated transcriptional programs is a common feature of HSCs. Collectively, this work demonstrates the utility of the RA-CFP reporter line as a tool for the isolation of superior HSCs.
2018-06-21 | GSE108155 | GEO
Project description:Self-renewal is a defining characteristic of stem cells, however the molecular pathways underlying its regulation are poorly understood. Here we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell cycle regulators, normally expressed in non-self-renewing multipotent progenitors. Experiment Overall Design: LT-HSC (Lin-cKit+Sca1+CD34-CD135-) and ST-HSC (Lin-cKit+Sca1+CD34+CD135-) cells were prospectively sorted from the BM of MxCre-.Pbx1f/f control mice harvested 4 weeks after the last injection of poly(I:C).
2008-06-20 | E-GEOD-9189 | biostudies-arrayexpress
Project description:Hematopoietic stem cells (HSC) activity is tightly controlled to ensure the integrity of the hematopoietic system during the organism’s lifetime. How the HSC compartment maintains its long-term fitness in condition of chronic stresses associated with systemic metabolic disorders is poorly understood. In this study, we show that obesity functionally affects the long-term function of the most immature engrafting HSC subpopulation. We link this altered regenerative activity to the oxidative stress and the aberrant constitutive activation of the AKT signaling pathway that characterized the obese environment. In contrast, we found minor disruptions of the HSC function in obese mice at steady state, suggesting that active mechanisms could protect the HSC compartment from its disturbed environment. Consistent with this idea, we found that FOXO proteins in HSCs isolated from obese mice become insensitive to their normal upstream regulators such as AKT, even during intense oxidative stress. We established that hyperglycemia, a key condition associated with obesity, is directly responsible for the alteration of the AKT-FOXO axis in HSCs and their abnormal oxidative stress response. As a consequence, we observed that HSCs isolated from a hyperglycemic environment display enhanced resistance to oxidative stress and DNA damage. Altogether, these results indicate that chronic metabolic stresses associated with obesity and/or hyperglycemia affect the wiring of the HSCs and modify their oxidative stress response. These data suggest that the uncoupling of FOXO to its environmental regulators could be a key adaptive strategy that promotes the survival of the HSC compartment in obesity.
2021-08-18 | GSE156085 | GEO
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.
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2013-08-13 | E-GEOD-39725 | biostudies-arrayexpress
Project description:HSC-3-5 cells were derived from human HSC-3 cells via transwell invasion assay. Transcriptional profiling of human HSC-3 cells comparing with high invasive HSC-3-5 cells. Goal was to determine the effects of invasion on global HSC-3-5 gene expression during tumor metastasis. Two-condition experiment, HSC-3 vs. HSC-3-5 cells.
2013-08-13 | E-GEOD-39723 | biostudies-arrayexpress
Project description:Obesity is a chronic organismal stress that disrupts multiple systemic and tissue-specific functions. Here, we describe the effects of established obesity on the activity of the hematopoietic stem cell (HSC) compartment. We show that obesity promotes the selection of a quiescent HSC subset primed for activation, leading to aberrant hematopoietic stress responses. We establish that the transcription factor Gfi1 is a key regulator of the HSC fate in obesity as its increased expression in obesity induces their abnormal activity. We demonstrate that these dysregulations are initially triggered by the chronic oxidative stress associated with obesity. Once acquired, we show that the impact of obesity on HSCs is long lasting and cannot be reversed by weight loss or transplantation. These results demonstrated that obesity promotes irreversible changes on the long-term fitness of the HSC compartment, a phenomenon that is likely to contribute to the hematopoietic dysregulations observed in obese patients.
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Project description:HSC-3-5 cells, which drived from human HSC-3 cells via transwell invasion assay was high invasive.Tumor cells were injected into the flank of SCID mice. After 6 weeks, transcriptional profiling of human HSC-3 tumor comparing with high invasive HSC-3-5 tumor. Goal was to determine the effects of invasion on global HSC-3-5 gene expression during tumor metastasis. HSC-3 and HSC-3-5 oral cancer cells were respectively injected into the flank and tongue of SCID mice. After 1 and 6 weeks, total RNA was respectively extracted from the tumor tissue on tongue and flank of SCID mice for gene expression profiling during metastasis. Briefly, two-condition experiment,HSC-3 vs. HSC-3-5 cells.
2013-08-13 | E-GEOD-39726 | biostudies-arrayexpress
Project description:Obesity is a chronic organismal stress that disrupts multiple systemic and tissue-specific functions. Here, we describe the effects of established obesity on the activity of the hematopoietic stem cell (HSC) compartment. We show that obesity promotes the selection of a quiescent HSC subset primed for activation, leading to aberrant hematopoietic stress responses. We establish that the transcription factor Gfi1 is a key regulator of the HSC fate in obesity as its increased expression in obesity induces their abnormal activity. We demonstrate that these dysregulations are initially triggered by the chronic oxidative stress associated with obesity. Once acquired, we show that the impact of obesity on HSCs is long lasting and cannot be reversed by weight loss or transplantation. These results demonstrated that obesity promotes irreversible changes on the long-term fitness of the HSC compartment, a phenomenon that is likely to contribute to the hematopoietic dysregulations observed in obese patients.
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