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Flt3- and Tie2-Cre tracing identifies regeneration in sepsis from multipotent progenitors but not hematopoietic stem cells

ABSTRACT: Increased hematopoietic stem cell (HSC) proliferation in response to infections might reflect enhanced HSC contributions for rapid replenishment of blood and immune cell compartments. However, there is no direct evidence in vivo for enhanced HSC differentiation to natural challenges. Here we studied by non-invasive fate mapping HSC differentiation for a comprehensive set of hematopoietic challenges, including irradiation, polymicrobial sepsis, bleeding, antibody-mediated ablation of granulocytes or B lymphocytes (akin to Rituximab in humans), and genetic lymphocyte deficiency. HSC sensed systemic infection, upregulated transcription factors promoting stem cell self-renewal (Foxp1, Atf4), stem cell maintenance (cMyc and nMyc), transcription in stressed cells (Hsf1) and suppression of apoptosis (E2f4), and enhanced their proliferation. However, none of these acute or chronic hematopoietic stressors enhanced HSC output in situ, suggesting HSC protection and maintenance rather than heightened differentiation. This disconnect may prioritize the long-term integrity of HSC over short-term enhanced productivity in response to hematopoietic perturbations.

ORGANISM(S): Mus musculus

PROVIDER: GSE193322 | GEO | 2022/12/05

REPOSITORIES: GEO

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Mitochondrial respiratory chain is essential for hematopoietic stem cell function

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2017-09-13 | PXD006054 | Pride

C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence

Project description:In blood, the transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver hematopoietic stem cells (HSCs). However, its function in adult HSCs is unknown. Here, using an inducible knockout model, we found that C/EBPa deficient adult HSCs underwent a pronounced expansion with enhanced proliferation, characteristics resembling fetal liver HSCs. Consistently, transcription profiling of C/EBPa deficient HSCs revealed a gene expression program similar to fetal liver HSCs. Moreover we observed that age-specific C/EBPa expression correlated with its inhibitory effect on the HSC cell cycle. Mechanistically, we identified N-Myc as a C/EBPa downstream target. C/EBPa upregulation during HSC transition from an active fetal state to a quiescent adult state was accompanied by down-regulation of N-Myc, and loss of C/EBPa resulted in de-repression of NMyc. Our data establish that C/EBPa acts as a molecular switch between fetal and adult states of HSC in part via transcriptional repression of the proto-oncogene N-Myc. HSCs of Pu.1 knock-in (PU.1ki/ki) mice were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the corresponding wild type.

2012-11-14 | E-GEOD-42234 | biostudies-arrayexpress

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Project description:The molecular mechanisms that drive hematopoietic stem cell (HSC) functional decline under conditions of stress are not completely understood. Here, in light of the recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells (HSCs) under telomeric stress, as that induced by pathogenic germline mutations in telomerase complex genes. These analyses revealed that telomere attrition maintains HSCs in a state of persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of interferon (IFN) signaling response, which directly comprises HSCs’ self-renewal capabilities and eventually leads to their exhaustion. Telomerase reactivation completely restored HSC transcriptional homeostasis at the single-cell level, overcame enhanced megakaryocytic differentiation and significantly ameliorated HSCs’ repopulation capacity in the setting of competitive transplantation, suggesting that HSCs can repristinate their function upon telomere damage resolution. This study challenges the long-standing hypothesis that telomere attrition limits the proliferative potential of HSCs by inducing apoptosis or senescence and suggests that early intervention targeting the IFN axis could prevent bone marrow failure syndromes in patients with pathogenic mutations affecting telomere maintenance.

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Hematopoiesis under telomeric attrition at the single-cell resolution

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de novo DNA Methylation Balances Hematopoietic Stem Cell Self-Renewal and Differentiation

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2011-09-30 | E-GEOD-27322 | biostudies-arrayexpress

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C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence

2012-11-14 | GSE42234 | GEO

Chaperone-mediated autophagy sustains hematopoietic stem cell function

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2021-03-05 | PXD022196 | Pride

Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes molecularly distinct from physiologic stem cell aging

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2011-05-06 | E-GEOD-27686 | biostudies-arrayexpress

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