Population snapshots predict early haematopoietic and erythroid hierarchies

Nature. 2018 Mar 1;555(7694):54-60. doi: 10.1038/nature25741. Epub 2018 Feb 21.

Abstract

The formation of red blood cells begins with the differentiation of multipotent haematopoietic progenitors. Reconstructing the steps of this differentiation represents a general challenge in stem-cell biology. Here we used single-cell transcriptomics, fate assays and a theory that allows the prediction of cell fates from population snapshots to demonstrate that mouse haematopoietic progenitors differentiate through a continuous, hierarchical structure into seven blood lineages. We uncovered coupling between the erythroid and the basophil or mast cell fates, a global haematopoietic response to erythroid stress and novel growth factor receptors that regulate erythropoiesis. We defined a flow cytometry sorting strategy to purify early stages of erythroid differentiation, completely isolating classically defined burst-forming and colony-forming progenitors. We also found that the cell cycle is progressively remodelled during erythroid development and during a sharp transcriptional switch that ends the colony-forming progenitor stage and activates terminal differentiation. Our work showcases the utility of linking transcriptomic data to predictive fate models, and provides insights into lineage development in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basophils / cytology
  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Cell Lineage / drug effects
  • Cell Lineage / genetics
  • Erythrocytes / cytology*
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Erythroid Precursor Cells / cytology*
  • Erythroid Precursor Cells / drug effects
  • Erythroid Precursor Cells / metabolism
  • Erythropoiesis* / drug effects
  • Female
  • Flow Cytometry
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Mast Cells / cytology
  • Mice
  • Proto-Oncogene Proteins c-kit / metabolism
  • RNA, Small Cytoplasmic / analysis
  • RNA, Small Cytoplasmic / genetics
  • Single-Cell Analysis
  • Transcriptome

Substances

  • Intercellular Signaling Peptides and Proteins
  • RNA, Small Cytoplasmic
  • Proto-Oncogene Proteins c-kit