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

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

PROVIDER: PRJNA659054 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12511114_1.fastq.gz	Fastqsanger.gz
	SRR12511114_2.fastq.gz	Fastqsanger.gz
	SRR12511115_1.fastq.gz	Fastqsanger.gz
	SRR12511115_2.fastq.gz	Fastqsanger.gz
	SRR12511116_1.fastq.gz	Fastqsanger.gz

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

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

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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

Project description:Mitochondrial Potentiation Ameliorates Age Related Heterogeneity in Hematopoietic Stem Cell Function

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

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Mitochondrial Potentiation Ameliorates Age Related Heterogeneity in Hematopoietic Stem Cell Function

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-19 | GSE156808 | GEO

Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway

Project description:Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

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Increased molecular and functional heterogeneity of hematopoietic stem cells contributes to age-related decline of tissue and body function

Project description:Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Previous studies have demonstrated that aged hematopoietic stem cells (HSCs) are functionally compromised, which at least partly contributes to aging-related decline of the body health. However, the underlying mechanism is largely unknown. Here we reveal a clear aging heterogeneity of old HSCs, which can be marked by the CD150 levels. Comparative molecular and functional analyses revealed that CD150high HSCs have an elder transcriptome, epigenome and diminished repopulation capacity in old mice when compared to CD150low HSCs. Mechanistically, CD150high HSCs from old mice have greatly compromised differentiation capacity compared to that of the CD150low HSCs. Importantly, decreasing the CD150high HSC ratio in old mice can alleviate aging-related functional decline. Thus, our study not only reveals how HSC heterogeneity contributes to aging, but also points to a potential way for rejuvenation.

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Increased molecular and functional heterogeneity of hematopoietic stem cells contributes to age-related decline of tissue and body function

Project description:Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Previous studies have demonstrated that aged hematopoietic stem cells (HSCs) are functionally compromised, which at least partly contributes to aging-related decline of the body health. However, the underlying mechanism is largely unknown. Here we reveal a clear heterogeneity of old HSCs, which can be marked by the CD150 levels. Comparative molecular and functional analyses revealed that CD150low HSCs from old mice have a younger aging clock, transcriptome, and better repopulation capacity compared to that of the CD150high HSCs. Mechanistically, CD150high HSCs from old mice have greatly compromised differentiation capacity compared to that of the CD150low HSCs. Importantly, decreasing the CD150high HSC ratio in old mice can alleviate aging-related functional decline. Thus, our study not only reveals how HSC heterogeneity contributes to aging, but also points to a potential way for rejuvenation.

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