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

Dev Cell. 2020 Oct 26;55(2):133-149.e6. doi: 10.1016/j.devcel.2020.07.015. Epub 2020 Aug 17.


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.

Keywords: IL1β; Nlrp3; endothelial-to-hematopoietic transition (EHT); hematopoietic stem cell (HSC); iPSC; inflammasome; inflammation; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural

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


  • Core Binding Factor Alpha 2 Subunit
  • Inflammasomes
  • RUNX1 protein, human