Megakaryocyte production is sustained by direct differentiation from erythromyeloid progenitors in the yolk sac until midgestation

• Published in: Immunity (Cambridge, Mass.) Mass.), 2021-07, Vol.54 (7), p.1433-1446.e5
• Main Authors: Iturri, Lorea, Freyer, Laina, Biton, Anne, Dardenne, Pascal, Lallemand, Yvan, Gomez Perdiguero, Elisa
• Format: Article
• Language: English
• Subjects: Colonization; Development Biology; Differentiation; Efficiency; embryo; Embryos; Endothelium; Erythrocytes; erythropoiesis; fate mapping; fetal liver; Fetuses; Flow cytometry; Gene expression; hematopoiesis; Hematopoietic stem cells; Heterogeneity; Labeling; Leukocytes (granulocytic); Life Sciences; Liver; Macrophages; Mast cells; Megakaryocytes; megakaryopoiesis; Monocytes; Population; Progenitor cells; resident macrophages; scRNAseq; Stem cells; Yolk; Yolk sac
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.04.026

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, monocytes, granulocytes, mast cells and macrophages, the latter in a Myb transcription factor-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 Myb-dependent bipotent progenitors expressing Csf2rb and colonize the fetal liver, where they give rise to megakaryocytes and to large numbers of erythrocytes. Understanding megakaryocyte development is crucial as they play key functions during vascular development, in particular in separating blood and lymphatic networks. [Display omitted] •EMP produce locally committed progenitors prior to fetal liver colonization•Two sequential waves of EMP differentiation revealed at the single cell level•Yolk sac Mk develop mainly from EMPs in a Myb-independent manner•CD131 identifies Myb-dependent EMP-derived MEP progenitors in the yolk sac The yolk sac produces the first blood cells during embryonic development. Iturri et al. now show the extent of local definitive hematopoietic differentiation occurring in this organ before colonization of the fetal liver and demonstrate the existence of a direct pathway of megakaryopoiesis produced by EMPs, independently of hematopoietic stem cells.