Distinct myeloid progenitor differentiation pathways identified through single cell RNA sequencing

According to current models for hematopoiesis, lymphoid-primed multi-potent progenitors (LMPPs; Lin(−)Sca-1(+)c-Kit(+)CD34(+)Flt3(hi)) and common myeloid progenitors (CMPs; Lin(−)Sca-1(+)c-Kit(+)CD34(+)CD41(hi)) establish an early branch point for separate lineage commitment pathways from hematopoietic stem cells, with the notable exception that both pathways are proposed to generate all myeloid innate immune cell types through the same myeloid-restricted pre-granulocyte-macrophage progenitor (pre-GM; Lin(−)Sca-1(−)c-Kit(+)CD41(−)FcγRII/III(−)CD150(−)CD105(−)). By single cell transcriptome profiling of pre-GMs we identify distinct myeloid differentiation pathways: a Gata1-expressing pathway generates mast cells, eosinophils, megakaryocytes and erythroid cells, and a Gata1-negative pathway that generates monocytes, neutrophils and lymphocytes. These results identify an early hematopoietic lineage bifurcation, separating the myeloid lineages prior to their segregation from other hematopoietic lineage potentials.