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Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis

ABSTRACT: RNA-sequencing was performed to look for transcriptional differences between wild-type and Mpc2-deficient granulocyte-macrophage progenitors. Very few genes were dysregulated in knockout cells relative to wild-type. Gls Mpc2 double knockouts were additionally analyzed to examine extent of Gls and Mpc2 deletion relative to single knockouts. Paper abstract: Hematopoietic homeostasis is maintained by stem and progenitor cells in part by extrinsic feedback cues triggered by mature cell loss. We demonstrate a different mechanism by which hematopoietic progenitors intrinsically anticipate and prevent the loss of mature progeny through metabolic switches. We examined hematopoiesis in mice conditionally deficient in long-chain fatty acid oxidation (carnitine palmitoyltransferase 2, Cpt2), glutaminolysis (glutaminase, Gls), or mitochondrial pyruvate import (mitochondrial pyruvate carrier 2, Mpc2). While genetic ablation of Cpt2 or Gls minimally impacted most blood lineages, deletion of Mpc2 led to a sharp decline in mature myeloid cells. However, MPC2-deficient myeloid cells rapidly recovered due to a transient increase in myeloid progenitor proliferation. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was intrinsic to MPC2-deficient progenitors and accompanied by a metabolic switch to glutaminolysis. Thus, hematopoietic progenitors intrinsically adjust to metabolic perturbations independently of feedback from downstream mature cells to maintain homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE184548 | GEO | 2021/09/27

REPOSITORIES: GEO

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Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis

Project description:RNA-sequencing was performed to look for transcriptional differences between wild-type and Mpc2-deficient granulocyte-macrophage progenitors immediately following the deletion of Mpc2. Paper abstract: Hematopoietic stem and progenitor cells likely engage specific metabolic pathways to promote homeostasis of downstream mature lineages. We examined hematopoiesis in mice conditionally deficient in genes required for long-chain fatty acid oxidation (Cpt2), glutaminolysis (Gls), or mitochondrial pyruvate import (Mpc2). Genetic ablation of Cpt2 or Gls minimally impacted most blood lineages. Deletion of Mpc2 led to a sharp decline in mature myeloid cells and a slower reduction in T cells, whereas other hematopoietic lineages were unaffected. Yet MPC2-deficient monocytes and neutrophils rapidly recovered due to a transient increase in proliferation of myeloid but not other progenitors. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was progenitor-intrinsic and accompanied by a metabolic switch to glutaminolysis. Myeloid recovery after loss of MPC2 or cyclophosphamide treatment was delayed in the absence of GLS. Reciprocally, MPC2 was not required for myeloid recovery after cyclophosphamide treatment. Thus, whereas mitochondrial pyruvate metabolism maintains myelopoiesis under steady-state conditions, rapid recovery from acute loss of myeloid cells requires a switch to glutaminolysis in progenitors.

2023-02-22 | GSE225578 | GEO

Expression data from pulmonary arterial endothelial cells treated with siRNA control or siGLS in stiff or soft matrix

Project description:Dysregulation of vascular stiffness and cellular metabolism occur early in pulmonary hypertension (PH). Yet, the mechanisms by which biophysical properties of extracellular matrix relate to metabolic processes and downstream PH phenotypes remain undefined. In cultured endothelial and smooth muscle cells and confirmed in PH-diseased human samples, we found that ECM stiffening activates the mechanosensitive factors YAP/TAZ to increase glycolysis and induce glutaminase (GLS) expression and glutaminolysis. Glutaminolysis replenishes aspartate for anabolic biosynthesis, thus sustaining proliferation and migration within stiff ECM. In vitro GLS inhibition blocks aspartate production, consequently reprogramming entire cellular proliferative pathways, while aspartate restores proliferation. In a rat model in vivo, GLS inhibition prevents hemodynamic and histologic manifestations of PH. Thus, mechanical ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis â a paradigm that advances our understanding of the connections of mechanical stimuli with dysregulated vascular metabolism and identifies new metabolic drug targets in PH. We used microarrays to decipher the global program of gene expression involved in response to matrix stiffening and determined the implication of glutaminolysis (GLS) in these process PAECs were transfected with an siRNA control (siNC) or a siRNA against GLS (siGLS) and cultivated on soft hydrogel (1kPa) or stiff hydrogel (50kPa). After 48h of transfection cells were lysate and RNA extract for hybridization on Affymetrix microarrays.

2016-09-01 | E-GEOD-75793 | biostudies-arrayexpress

Expression data from pulmonary arterial endothelial cells treated with siRNA control or siGLS in stiff or soft matrix

Project description:Dysregulation of vascular stiffness and cellular metabolism occur early in pulmonary hypertension (PH). Yet, the mechanisms by which biophysical properties of extracellular matrix relate to metabolic processes and downstream PH phenotypes remain undefined. In cultured endothelial and smooth muscle cells and confirmed in PH-diseased human samples, we found that ECM stiffening activates the mechanosensitive factors YAP/TAZ to increase glycolysis and induce glutaminase (GLS) expression and glutaminolysis. Glutaminolysis replenishes aspartate for anabolic biosynthesis, thus sustaining proliferation and migration within stiff ECM. In vitro GLS inhibition blocks aspartate production, consequently reprogramming entire cellular proliferative pathways, while aspartate restores proliferation. In a rat model in vivo, GLS inhibition prevents hemodynamic and histologic manifestations of PH. Thus, mechanical ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis – a paradigm that advances our understanding of the connections of mechanical stimuli with dysregulated vascular metabolism and identifies new metabolic drug targets in PH. We used microarrays to decipher the global program of gene expression involved in response to matrix stiffening and determined the implication of glutaminolysis (GLS) in these process

2016-09-01 | GSE75793 | GEO

Expression data of Rag2-deficient Ets1++ and Rag2-deficient Ets1-- mature NK cells and WT bone marrow progenitors

Project description:Expression profiling of Rag2-deficient Ets1++ and Rag2-deficient Ets1-- mature NK cells and WT bone marrow progenitors, WT T cells, and WT Pro B cells WT Hematopoietic progenitors, CD4 T cells, Pro B cells, and WT and Ets1-deficient NK cells were FACs sorted. RNA was subsequently extracted, labelled, and hybridized to Affymetrix microarrays. The goal if this experiment was to identify Ets1 dependent genes in NK cells

2012-08-09 | E-GEOD-37301 | biostudies-arrayexpress

Inhibiting MYC-regulated Glutaminase Metabolic Axis is an Effective Synthetic Lethal Approach for Treating Chemoresistant Cancers

Project description:Amplification and expression of the MYC oncogene in tumor cells, including ovarian cancer cells correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. We have discovered that ovarian cancer cells overexpressing glutaminase (GLS), a MYC target and a key enzyme in glutaminolysis, are intrinsically resistant to platinum chemotherapy, and are enriched in the intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh 10 cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. Our findings suggest that applying a combined therapy of GLS inhibitor and PARP inhibitor could effectively treat chemoresistant ovarian cancers, especially those with high GLS expression.

2020-07-23 | GSE154941 | GEO

Brain tumor stem cell dependence on glutaminase reveals a metabolic vulnerability through the amino acid deprivation response pathway

Project description:Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSCs) has not yet been elucidated. Here we report that, across a panel of twenty glioblastoma BTSC lines, glutaminase (GLS) inhibition showed a variable response – from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with the expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered these cells susceptible to GLS inhibition, triggering the AADR, and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs, support the therapeutic targeting of the upstream activators and downstream effectors of the AADR pathway in GBM, and demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.

2020-12-25 | GSE155300 | GEO

Gene expression of Mirc11-/- hematopoietic myeloid progenitors

Project description:Compared gene expression between Lin-Sca1-cKit+ myeloid progenitors isolated from the bone marrow of 6-8 week old wildtype and Mirc11-/- mice. Previously observed that overexpression of Mirc11 in hematopoietic progenitors increased myeloid differentiation whereas loss of Mirc11 decreased myeloid differentiation. Performed RNA-seq to identify potential genes involved in myeloid differentiation regulated by Mirc11. Gene expression analysis of Mirc11 deficient myeloid progenitors revealed a decrease in Toll like receptor and interferon signaling. This anti-inflammatory phenotype was further observed in mature cells as Mirc11-/- bone marrow derived macrophages (BMDMs) have an attenuated response to inflammatory lip-opolysaccharide (LPS).

2020-11-18 | GSE160214 | GEO

Mass spectrometry analysis of mouse hematopoietic stem cells and their progenitors reveals differential expression within and between proteome and transcriptome throughout adult and aged hematopoiesis

Project description:mass spectrometry analysis of aged and adult hematopoietic stem cells, multipotent progenitors and oligopotent progenitors

2021-07-24 | PXD017442 | Pride

Regeneration of immunocompetent B lymphopoiesis from pluripotent stem cells guided by transcription factors

Project description:We identified that the coordinated expression of exogenous transcription factors(Lhx2, Hoxa9, and Runx1), efficiently guides PSC-derived hematopoietic progenitors (iHPC) preferentially towards B cell lineage commitment, which successfully regenerate B lymphopoiesis in B-cell deficient animals. Of note, the abundancy of in vivo lymphopoiesis includes pro/pre-B progenitors, immature B cells, and all subsets of mature B1a, B1b, FO B and MZ B reconstitution in vivo. We performed single-cell RNA-Seq using the sorted GFP+CD45+ Lin- cells from the bone marrow of recipients at day 7.5 after iHPC transplantation.

2021-12-16 | GSE180319 | GEO

Regeneration of immunocompetent B lymphopoiesis from pluripotent stem cells guided by transcription factors

Project description:We identified that the coordinated expression of exogenous transcription factors efficiently guides PSC-derived hematopoietic progenitors (iHPC) preferentially towards B cell lineage commitment, which successfully regenerate B lymphopoiesis in B-cell deficient animals. Of note, the abundancy of in vivo lymphopoiesis includes pro/pre-B progenitors, immature B cells, and all subsets of mature B1a, B1b, FO B and MZ B reconstitution in vivo. We performed BCR deep sequencing using the sorted naive follicular B cells from the spleen of one recipient at week 4 after iHPC transplantation and one C57BL/6 mouse as control.

2021-12-16 | GSE180318 | GEO

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