Two Sequential and Independent Pathways of Erythromyeloid Progenitor Commitment in Their Niche of Emergence

The extra-embryonic yolk sac contains the first definitive multipotent hematopoietic cells, denominated erythromyeloid progenitors. They originate in situ prior to the emergence of hematopoietic stem cells and give rise to erythroid, monocyte/granulocytes, mast cells and macrophages, the latter in a Myb-independent manner. We uncovered here the heterogeneity of yolk sac erythromyeloid progenitors, at the single cell level, and discriminated multipotent from committed progenitors, prior to fetal liver colonization. We identified two temporally distinct megakaryocyte differentiation pathways. The first occurs in the yolk sac, bypasses intermediate bipotent megakaryocyte-erythroid progenitors and, similar to the differentiation of macrophages, is Myb-independent. By contrast, the second originates later, from bipotent progenitors and is absent in Myb-deficient embryos. We identified Csf2rb as a novel marker of these Myb-dependent megakaryocyte-erythroid bipotent progenitors that colonize the fetal liver, where they give rise to megakaryocytes and to large numbers of erythrocytes.