Rate of Progression through a Continuum of Transit-Amplifying Progenitor Cell States Regulates Blood Cell Production

The nature of cell-state transitions during the transit-amplifying phases of many developmental processes—hematopoiesis in particular—is unclear. Here, we use single-cell RNA sequencing to demonstrate a continuum of transcriptomic states in committed transit-amplifying erythropoietic progenitors, which correlates with a continuum of proliferative potentials in these cells. We show that glucocorticoids enhance erythrocyte production by slowing the rate of progression through this developmental continuum of transit-amplifying progenitors, permitting more cell divisions prior to terminal erythroid differentiation. Mechanistically, glucocorticoids prolong expression of genes that antagonize and slow induction of genes that drive terminal erythroid differentiation. Erythroid progenitor daughter cell pairs have similar transcriptomes with or without glucocorticoid stimulation, indicating largely symmetric cell division. Thus, the rate of progression along a developmental continuum dictates the absolute number of erythroid cells generated from each transit-amplifying progenitor, suggesting a paradigm for regulating the total output of differentiated cells in numerous other developmental processes. Li et al. utilize single-cell RNA-seq and functional assays to demonstrate erythropoiesis progresses through a continuum of both transcriptomic and phenotypic states. Perturbation of developmental progression through this continuum with glucocorticoid steroids reveals differentiation speed can be uncoupled from cell-cycle progression, generating greater numbers of erythrocytes.