Differences in cell cycle status underlie transcriptional heterogeneity in the HSC compartment
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA422622 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6381490.fastq.gz | Fastqsanger.gz | |||
| SRR6381500.fastq.gz | Fastqsanger.gz | |||
| SRR6381491.fastq.gz | Fastqsanger.gz | |||
| SRR6381501.fastq.gz | Fastqsanger.gz | |||
| SRR6381492.fastq.gz | Fastqsanger.gz |
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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).
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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.
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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: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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