Single-cell analyses reveal the clonal and molecular aetiology of Flt3L-induced emergency dendritic cell development

Nat Cell Biol. 2021 Mar;23(3):219-231. doi: 10.1038/s41556-021-00636-7. Epub 2021 Mar 1.

Abstract

Regulation of haematopoietic stem and progenitor cell (HSPC) fate is crucial during homeostasis and under stress conditions. Here we examine the aetiology of the Flt3 ligand (Flt3L)-mediated increase of type 1 conventional dendritic cells (cDC1s). Using cellular barcoding we demonstrate this occurs through selective clonal expansion of HSPCs that are primed to produce cDC1s and not through activation of cDC1 fate by other HSPCs. In particular, multi/oligo-potent clones selectively amplify their cDC1 output, without compromising the production of other lineages, via a process we term tuning. We then develop Divi-Seq to simultaneously profile the division history, surface phenotype and transcriptome of individual HSPCs. We discover that Flt3L-responsive HSPCs maintain a proliferative 'early progenitor'-like state, leading to the selective expansion of multiple transitional cDC1-primed progenitor stages that are marked by Irf8 expression. These findings define the mechanistic action of Flt3L through clonal tuning, which has important implications for other models of 'emergency' haematopoiesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Hematopoiesis / drug effects*
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / metabolism
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Male
  • Membrane Proteins / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenotype
  • RNA-Seq*
  • Single-Cell Analysis*
  • Transcriptome / drug effects*

Substances

  • Interferon Regulatory Factors
  • Membrane Proteins
  • flt3 ligand protein
  • interferon regulatory factor-8