Repetitive Elements Trigger RIG-I-like Receptor Signaling that Regulates the Emergence of Hematopoietic Stem and Progenitor Cells

Immunity. 2020 Nov 17;53(5):934-951.e9. doi: 10.1016/j.immuni.2020.10.007. Epub 2020 Nov 6.


Inflammatory signaling is required for hematopoietic stem and progenitor cell (HSPC) development. Here, we studied the involvement of RIG-I-like receptors (RLRs) in HSPC formation. Rig-I or Mda5 deficiency impaired, while Lgp2 deficiency enhanced, HSPC emergence in zebrafish embryos. Rig-I or Mda5 deficiency reduced HSPC numbers by inhibiting inflammatory signals that were in turn enhanced in Lgp2 deficient embryos. Simultaneous reduction of Lgp2 and either Rig-I or Mda5 rescued inflammatory signals and HSPC numbers. Modulating the expression of the signaling mediator Traf6 in RLR deficient embryos restored HSPC numbers. Repetitive element transcripts could be detected in hemogenic endothelial cells and HSPCs, suggesting a role as RLR ligands. Indeed, ectopic expression of repetitive elements enhanced HSPC formation in wild-type, but not in Rig-I or Mda5 deficient embryos. Manipulation of RLR expression in mouse fetal liver HSPCs indicated functional conservation among species. Thus, repetitive elements transcribed during development drive RLR-mediated inflammatory signals that regulate HSPC formation.

Keywords: HSCs; RIG-I-like receptors; development; hematopoiesis; hematopoietic stem cells; inflammation; innate immune receptors; repetitive elements; transposable elements; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Chromatin Assembly and Disassembly
  • DNA Transposable Elements
  • Disease Susceptibility
  • Gene Expression Regulation, Developmental*
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Immunity, Innate
  • Immunohistochemistry
  • Inflammation / etiology
  • Inflammation / metabolism
  • Inflammation / pathology
  • RNA Helicases / deficiency
  • RNA Helicases / genetics
  • RNA-Binding Proteins / metabolism
  • Repetitive Sequences, Nucleic Acid*
  • Signal Transduction*
  • TNF Receptor-Associated Factor 6 / metabolism
  • Valproic Acid / pharmacology
  • Zebrafish
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism*


  • Biomarkers
  • DNA Transposable Elements
  • RNA-Binding Proteins
  • TNF Receptor-Associated Factor 6
  • Zebrafish Proteins
  • ddx58 protein, zebrafish
  • Valproic Acid
  • DHX58 protein, human
  • RNA Helicases