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
  • Animals
  • Cell Differentiation/physiology
  • Core Binding Factor Alpha 2 Subunit/metabolism
  • Embryo, Nonmammalian/metabolism
  • Embryonic Development/physiology
  • Embryonic Stem Cells/metabolism*
  • Hematopoiesis/physiology
  • Hematopoietic Stem Cells/metabolism*
  • Humans
  • Induced Pluripotent Stem Cells/metabolism*
  • Inflammasomes/metabolism*
  • Zebrafish/embryology
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
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes