The effect of Glud1 inhibition of HSCs durgin ev vivo culture
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE279490 | GEO | 2026/07/13
REPOSITORIES: GEO
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Project description:Self-renewing hematopoietic stem cells (HSCs) during hematopoietic regeneration showed lower intracellular glutamate (Glu) levels compared with dividing progenitor cells in the steady state and HSCs that attenuate stem cell features during ex vivo culture. Moreover, R162, an inhibitor of glutamine dehydrogenase (Glud1) that catabolize Glu into α-ketoglutarate, contributed to stem cell maintenance during HSC divisions. These data suggest that lower intracellular Glu levels during HSC division contributed to self-renewing divisions by suppressing Glud1-mediated reactions.
2026-07-13 | GSE279409 | GEO
Project description:Self-renewing hematopoietic stem cells (HSCs) during hematopoietic regeneration showed lower intracellular glutamate (Glu) levels compared with dividing progenitor cells in the steady state and HSCs that attenuate stem cell features during ex vivo culture. Moreover, R162, an inhibitor of glutamine dehydrogenase (Glud1) that catabolize Glu into α-ketoglutarate, contributed to stem cell maintenance during HSC divisions. These data suggest that lower intracellular Glu levels during HSC division contributed to self-renewing divisions by suppressing Glud1-mediated reactions.
2026-07-13 | GSE279407 | GEO
Project description:Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase Cdc42. Here we demonstrate, using a comprehensive set of paired daughter cell analyses that include single cell 3D-confocal imaging, single cell transplants, single cell RNA-seq as well as single cell ATAC-seq, that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells.
2018-12-04 | GSE116707 | GEO
Project description:Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase Cdc42. Here we demonstrate, using a comprehensive set of paired daughter cell analyses that include single cell 3D-confocal imaging, single cell transplants, single cell RNA-seq as well as single cell ATAC-seq, that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells.
2018-12-04 | GSE116708 | GEO
Project description:Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the TCA cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH reducing equivalents into the mitochondria induced compartment-specific NAD+/NADH ratio shifts. MAS activity restoration or directly altering NAD+/NADH ratios normalised myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment specific metabolic brake on MuSC differentiation.
2024-07-02 | GSE243640 | GEO
Project description:To guarantee blood supply throughout adult life hematopoietic stem cells (HSCs) need to carefully balance between self-renewing cell divisions and quiescence. Identification of genes controlling HSC self-renewal is of utmost importance given that HSCs are the only stem cells with broad clinical applications. Transcription factor PU.1 is one of the major regulators of myeloid and lymphoid development. Recent reports suggest that PU.1 mediates its functions via gradual expression level changes rather than binary on/off states. So far, this has not been considered in any study of HSCs and thus, PU.1’s role in HSC function has remained largely unclear. Here we demonstrate using hypomorphic mice with an engineered disruption of an autoregulatory feedback loop that decreased PU.1 levels resulted in loss of key HSC functions, all of which could be fully rescued by restoration of proper PU.1 levels via a human PU.1 transgene. Mechanistically, we found excessive HSC cell divisions and altered expression of cell cycle regulators whose promoter regions were bound by PU.1 in normal HSCs. Adequate PU.1 levels were maintained by a mechanism of direct autoregulation restricted to HSCs through a physical interaction of a -14kb enhancer with the proximal promoter. Our findings identify PU.1 as novel regulator controling the switch between cell division and quiescence in order to prevent exhaustion of HSCs. Given that even moderate level changes greatly impact stem cell function, our data suggest important therapeutic implications for leukemic patients with reduced PU.1 levels. Moreover, we provide first proof, that autoregulation of a transcription factor, PU.1, has a crucial function in vivo. We anticipate that our concept of how autoregulation forms an active chromosomal conformation will impact future research on transcription factor networks regulating stem cell fate. 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.
2011-12-01 | E-GEOD-33031 | biostudies-arrayexpress
Project description:Glud1 (glutamate dehydrogenase 1) transgenic mice release more excitatory neurotransmitter glutamate to synaptic cleft throughout lifespan and show signs of accelerated aging. Here we compared transcriptomic profiles of these animals to their wild-type counterparts. The hippocampus was used for the analysis. Keywords: transgenic analysis Three Glud1 transgenic mice vs. three age-matched wide-type mice. Age: 9-month-old. Tissue: hippocampus.
2010-07-12 | E-GEOD-11419 | biostudies-arrayexpress
Project description:Glud1 (Glutamate dehydrogenase 1) transgenic mice release more excitatory neurotransmitter glutamate to synaptic cleft throughout lifespan. Here we compared transcriptomic profiles of these animals to their wild-type counterparts across 5 ages. The hippocampus was used for the analysis. Longitudinal studies of Glud1 transgenic and wide-type mice across 5 age points: 10 days post birth, 4.5 mo, 9 mo, 14.5 mo, and 20 mo.
2014-07-31 | E-GEOD-48911 | biostudies-arrayexpress
Project description:Adult hematopoietic stem cells (HSCs) sustain the lifelong production of all mature blood and immune cells. HSCs possess extensive regenerative potential, but the actual self-renewal of HSCs is limited. A long-standing question has been why replicative history negatively impacts HSC lineage-generating capacity. We found that accrued divisions durably alter HSC production; generating low-output bone-marrow landscapes that are highly variable in both lineage contribution and transcriptional divergence within individual lineages. Mechanistically, division-driven functional alterations in HSCs are due to redirecting branched chain amino acid (BCAA) usage from catabolic towards anabolic activity, causing faster HSC cell-cycle kinetics. Adding a BCAA deaminated product is sufficient to bypass the BCAA catabolic checkpoint and slow down the cell cycle, durably rescuing balanced lineage output of HSCs with accrued divisions. Hence, our study suggests a novel paradigm whereby replicative history causes metabolic and transcriptional drift, generating divergent HSC output. Division-dependent HSC functional drift can be restored by metabolite replacement, which has long-term therapeutic implications for HSC regenerative medicine.
2026-05-15 | GSE256530 | GEO
Project description:Adult hematopoietic stem cells (HSCs) sustain the lifelong production of all mature blood and immune cells. HSCs possess extensive regenerative potential, but the actual self-renewal of HSCs is limited. A long-standing question has been why replicative history negatively impacts HSC lineage-generating capacity. We found that accrued divisions durably alter HSC production; generating low-output bone-marrow landscapes that are highly variable in both lineage contribution and transcriptional divergence within individual lineages. Mechanistically, division-driven functional alterations in HSCs are due to redirecting branched chain amino acid (BCAA) usage from catabolic towards anabolic activity, causing faster HSC cell-cycle kinetics. Adding a BCAA deaminated product is sufficient to bypass the BCAA catabolic checkpoint and slow down the cell cycle, durably rescuing balanced lineage output of HSCs with accrued divisions. Hence, our study suggests a novel paradigm whereby replicative history causes metabolic and transcriptional drift, generating divergent HSC output. Division-dependent HSC functional drift can be restored by metabolite replacement, which has long-term therapeutic implications for HSC regenerative medicine.
2026-05-15 | GSE256529 | GEO