Internal medicine

Cellular differentiation

Progenitor cell

Population

Transcription factor

Biology

Gene

Haematopoiesis

Cell fate determination

Immunology

Anemia

Stem cell

Erythropoiesis

Blood cell

Cell biology

Genetics

Medicine

Environmental health

Nature

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. Single-cell transcriptomics, fate assays and a computational theory enable prediction of cell fates during haematopoiesis, discovery of regulators of erythropoiesis and reveal coupling between the erythroid, basophil and mast cell fates. Allon Klein, Merav Socolovsky and colleagues examine the emergence of distinct blood cell lineages from mouse haematopoietic progenitors. Their approach combines single-cell transcriptomics, cell fate potential assays and population balance analysis—a computational method for predicting cell fate probabilities from population snapshots. They use a new flow-cytometry strategy to sort cells with newly defined markers of erythroid differentiation and validate the findings at the single-cell level. The results show that differentiation is a continuous, albeit hierarchical, process. They also reveal that erythroid and mast cell fates are coupled, and that remodelling the expression of cell cycle regulators is very important as erythroid cells proceed to terminal differentiation.

Population snapshots predict early haematopoietic and erythroid hierarchies