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

Dev Cell. 2019 Apr 8;49(1):118-129.e7. doi: 10.1016/j.devcel.2019.01.026. | PubMed

Hojun Li¹, Anirudh Natarajan², Jideofor Ezike³, M Inmaculada Barrasa², Yenthanh Le², Zoë A Feder², Huan Yang², Clement Ma⁴, Styliani Markoulaki², Harvey F Lodish⁵

1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
2. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
3. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
4. Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center, Boston, MA 02215, USA.
5. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: lodish@wi.mit.edu.

Abstract

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.

Presented By Hojun Li