From hematopoietic trees to differentiation landscapes
The classic tree-like model that describes hematopoiesis assumes a stepwise loss of lineage potential with differentiation from hematopoietic stem cells to lineage-committed progenitors (Figure 2A). However, assignment of the MC differentiation trajectory to either the granulocyte-monocyte or the megakaryocyte-erythrocyte branch is a controversial topic. Studies supporting the idea that MCs belong to either branch have been presented 37-42. On a different angle, other investigations propose that MCs branch off early – close to hematopoietic stem cells – and differentiate along a unique trajectory 43,44.
Advances in high-throughput single-cell RNA sequencing and computational biology are now delineating the MC differentiation trajectory by suggesting a revision of the hematopoietic model 45. The idea to reconstruct hematopoietic differentiation with single-cell transcriptomics is based on capturing a snapshot of single differentiating progenitors 46. Such analysis reveals that differentiating cells traverse a continuous landscape of states, from multi- and bipotent progenitors to lineage committed cells (Figure 2B). A single-cell transcriptional landscape of bone marrow hematopoiesis in mouse shows that the MC developmental trajectory is positioned adjacent to the erythrocyte and basophil trajectories40,47. The MC and basophil trajectories are particularly close to each other 47,48, which indicates the presence of a bipotent basophil-MC progenitor population, a finding that is recapitulated in single-cell fate assay experiments38,47-49. Cell fate assays of mouse bone marrow progenitors also verified that basophil/MC differentiation is closely coupled with erythropoiesis 40. The combination of single-cell transcriptomics and lineage tracing provides even deeper insights into hematopoiesis with focus on MC differentiation. Tracing individually barcoded mouse hematopoietic progenitor cells duringin vitro culture confirms a coupling between MC and basophil fates as well as between MC and erythrocyte fates 50. A link between basophil/MC progenitors and erythrocyte progenitors has also been proposed in human hematopoiesis 51-54. Thus, single-cell RNA sequencing has revolutionized our understanding of MC differentiation. The data reveals an overall landscape of hematopoiesis and an association between the MC, erythrocyte and basophil granulocyte differentiation trajectories.
In summary, the landscape model of hematopoiesis unifies old and new theories of the MC differentiation field and constitutes a foundation for future research.