PUBLICATION

Metabolic Regulation of Inflammasome Activity Controls Embryonic Hematopoietic Stem and Progenitor Cell Production

Authors
Frame, J.M., Kubaczka, C., Long, T.L., Esain, V., Soto, R.A., Hachimi, M., Jing, R., Shwartz, A., Goessling, W., Daley, G.Q., North, T.E.
ID
ZDB-PUB-200819-14
Date
2020
Source
Developmental Cell   55(2): 133-149.e6 (Journal)
Registered Authors
Goessling, Wolfram, North, Trista
Keywords
IL1β, Nlrp3, endothelial-to-hematopoietic transition (EHT), hematopoietic stem cell (HSC), iPSC, inflammasome, inflammation, zebrafish
MeSH Terms
  • Embryo, Nonmammalian/metabolism
  • Animals
  • Humans
  • Core Binding Factor Alpha 2 Subunit/metabolism
  • Inflammasomes/metabolism*
  • Zebrafish/embryology
  • Embryonic Development/physiology
  • Cell Differentiation/physiology
  • Hematopoietic Stem Cells/metabolism*
  • Hematopoiesis/physiology
  • Embryonic Stem Cells/metabolism*
  • Induced Pluripotent Stem Cells/metabolism*
(all 12)
PubMed
32810442 Full text @ Dev. Cell
Abstract
Embryonic hematopoietic stem and progenitor cells (HSPCs) robustly proliferate while maintaining multilineage potential in vivo; however, an incomplete understanding of spatiotemporal cues governing their generation has impeded robust production from human induced pluripotent stem cells (iPSCs) in vitro. Using the zebrafish model, we demonstrate that NLRP3 inflammasome-mediated interleukin-1-beta (IL1β) signaling drives HSPC production in response to metabolic activity. Genetic induction of active IL1β or pharmacologic inflammasome stimulation increased HSPC number as assessed by in situ hybridization for runx1/cmyb and flow cytometry. Loss of inflammasome components, including il1b, reduced CD41+ HSPCs and prevented their expansion in response to metabolic cues. Cell ablation studies indicated that macrophages were essential for initial inflammasome stimulation of Il1rl1+ HSPCs. Significantly, in human iPSC-derived hemogenic precursors, transient inflammasome stimulation increased multilineage hematopoietic colony-forming units and T cell progenitors. This work establishes the inflammasome as a conserved metabolic sensor that expands HSPC production in vivo and in vitro.
Genes / Markers
Figures
Figure Gallery (3 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WTchemical treatment by environment: glucosePrim-25
WTchemical treatment by environment: glucoseDay 5
WTchemical treatment by environment: glucoseDay 5
WTchemical treatment by environment: glucoseDay 5
WTchemical treatment by environment: hydrogen peroxidePrim-25
WTchemical treatment by environment: metronidazole, chemical treatment by environment: nigericinProtruding-mouth
WTchemical treatment by environment: nigericinPrim-15
WTchemical treatment by environment: nigericinPrim-25
WTchemical treatment by environment: nigericinPrim-25
WTchemical treatment by environment: nigericinPrim-25
1 - 10 of 46
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
c264TgTransgenic Insertion
    gl22TgTransgenic Insertion
      gl23TgTransgenic Insertion
        gl24TgTransgenic Insertion
          hdb10TgTransgenic Insertion
          hdb12
            		Insertion
            i114TgTransgenic Insertion
              la2TgTransgenic Insertion
                pd27TgTransgenic Insertion
                  rw0410hTgTransgenic Insertion
                    1 - 10 of 20
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                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    caspaMO1-caspaMRPHLNO
                    il1bMO1-il1bMRPHLNO
                    il1rl1MO1-il1rl1MRPHLNO
                    il6MO1-il6MRPHLNO
                    nlrp3MO1-nlrp3MRPHLNO
                    nlrp3l.1MO1-nlrp3l.1MRPHLNO
                    nlrp3l.1MO2-nlrp3l.1MRPHLNO
                    pycardMO2-pycardMRPHLNO
                    spi1aMO2-spi1aMRPHLNO
                    spi1bMO1-spi1bMRPHLNO
                    1 - 10 of 10
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                    Fish
                    Fish
                    c264Tg; gl24Tg
                    c264Tg; gl24Tg; sd35Tg
                    caspahdb12/hdb12
                    caspahdb12/hdb12; la2Tg
                    la2Tg
                    la2Tg + MO1-caspa
                    la2Tg + MO1-il1b
                    pd27Tg; zf169Tg
                    pycardzf2174/zf2174
                    pycardzf2174/zf2174; la2Tg
                    1 - 10 of 22
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                    Antibodies
                    No data available
                    Orthology
                    No data available
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    CeruleanEFGCerulean
                    DsRedEFGDsRed
                    DsRed2EFGDsRed2
                    EGFPEFGEGFP
                    GAL4EFGGAL4
                    GFPEFGGFP
                    mAGFPEFGmAGFP
                    mCherryEFGmCherry
                    NTREFGNTR
                    TomatoEFGTomato
                    1 - 10 of 10
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                    Mapping
                    No data available
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                    Citation
                    Frame, J.M., Kubaczka, C., Long, T.L., Esain, V., Soto, R.A., Hachimi, M., Jing, R., Shwartz, A., Goessling, W., Daley, G.Q., North, T.E. (2020) Metabolic Regulation of Inflammasome Activity Controls Embryonic Hematopoietic Stem and Progenitor Cell Production. Developmental Cell. 55(2):133-149.e6.