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

Lin et al. examine the process of clonal tuning during Flt3L-mediated emergency haematopoiesis, which leads to selective expansion of haematopoietic stem and progenitor cells that are primed to produce type 1 conventional dendritic cells instead of modulating cell fate. 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.

Automated summary

The study examines the mechanism of clonal tuning during Flt3L-mediated emergency hematopoiesis, revealing the selective expansion of specific HSPC clones to increase the production of type 1 conventional dendritic cells without affecting other lineages. This is achieved through maintaining proliferative 'early progenitor'-like state in Flt3L-responsive HSPCs, leading to the expansion of transitional cDC1-primed progenitor stages marked by Irf8 expression. The findings define the mechanistic action of Flt3L through clonal tuning, which has important implications for emergency hematopoiesis models.