Yolk sac, but not hematopoietic stem cell–derived progenitors, sustain erythropoiesis throughout murine embryonic life

Abstract

In the embryo, the first hematopoietic cells derive from the yolk sac and are thought to be rapidly replaced by the progeny of hematopoietic stem cells. We used three lineage-tracing mouse models to show that, contrary to what was previously assumed, hematopoietic stem cells do not contribute significantly to erythrocyte production up until birth. Lineage tracing of yolk sac erythromyeloid progenitors, which generate tissue resident macrophages, identified highly proliferative erythroid progenitors that rapidly differentiate after intra-embryonic injection, persisting as the major contributors to the embryonic erythroid compartment. We show that erythrocyte progenitors of yolk sac origin require 10-fold lower concentrations of erythropoietin than their hematopoietic stem cell–derived counterparts for efficient erythrocyte production. We propose that, in a low erythropoietin environment in the fetal liver, yolk sac–derived erythrocyte progenitors efficiently outcompete hematopoietic stem cell progeny, which fails to generate megakaryocyte and erythrocyte progenitors.

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

“…Erythromyeloid progenitors (EMPs) are developmentally restricted hematopoietic progenitors that emerge from the hemogenic endothelium of the yolk sac and have the potential to give rise to definitive hematopoietic cells from both the erythroid and myeloid lineages ( Gomez Perdiguero et al., 2015 ; McGrath et al., 2015 ; Frame et al., 2016 ; Kasaai et al., 2017 ). While the extent of their contribution to fetal and adult hematopoietic systems is still under investigation, EMP-derived hematopoiesis is required for embryo survival through erythrocyte production until birth ( Chen et al., 2011 ; Soares-da-Silva et al., 2021 ) and for the generation of certain adult resident macrophage populations, such as brain microglia, liver Kupffer cells and epidermal Langerhans cells ( Gomez Perdiguero et al., 2015 ; Hoeffel et al., 2015 ), and adult resident mast cells ( Gentek et al., 2018 ; Li et al., 2018 ).…”

“…Importantly, while HSCs need to colonize the fetal liver in order to differentiate ( Godin et al., 1999 ; Kieusseian et al., 2012 ), EMPs can also differentiate in situ in the yolk sac at least into macrophages, but other lineages have not been formally investigated. EMPs then enter the bloodstream at the beginning of circulation and colonize the fetal liver, where they expand and differentiate into erythrocytes, megakaryocytes, macrophages, monocytes, granulocytes and mast cells ( Gomez Perdiguero et al., 2015 ; Hoeffel et al., 2015 ; McGrath et al., 2015 ; Gentek et al., 2018 ; Li et al., 2018 ; Stremmel et al., 2018 ; Soares-da-Silva et al., 2021 ).…”

Hematopoiesis during Ontogenesis, Adult Life, and Aging

“…In the first wave of hematopoiesis, three types of blood cell are produced, namely primitive erythrocytes expressing embryonic globins, and megakaryocytes and macrophages [5][6][7]. Yolk sac erythroid progenitor cells but not HSC descendants maintain erythropoiesis throughout the mouse embryogenesis (Figure 1B) [8]. This is related to the fact that to efficiently produce erythrocytes, yolk sac-derived precursors require 10 times lower erythropoietin concentrations than their HSC-derived counterparts.…”

“…In the absence of HSC activity, embryo viability prior to birth is maintained by hematopoietic cells derived from erythro-megakaryocytic progenitors (Figure 1C). [3,8,9].…”

Mds1, an inducible Cre allele specific to adult-repopulating hematopoietic stem cells

“…The efficacy of these CreER alleles relies on the timing of induction during the staggered emergence of HSC-independent progenitors and of HSCs. However, the significant temporal overlap in the emergence of HSC-independent progenitors and of HSCs, coupled with the broad cellular expression of these promoters, and the imprecision of in vivo CreER induction often results both in incomplete and in mixed labeling ( Gentek et al, 2018 ; Gomez Perdiguero et al, 2015 ; Hoeffel et al, 2015 ; Soares-da-Silva et al, 2021 ). An alternative approach is to specifically label emerging HSCs.…”