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.
Highlights
Erythrocytes are the most abundant cells in circulation
We show that hematopoietic stem cells (HSCs) do not contribute significantly to embryonic erythropoiesis by tracing Flt3+ progenitors or YFP-expressing cells in Cdh5CreERT2 Rosa26YFP induced in E10.5 embryos
Single-cell surface marker expression data from E14.5 fetal liver (FL) cells was projected as tSNE1 vs. tSNE2 (t-distributed stochastic neighbor embedding; Fig. 1 A), and three major clusters were defined by the expression of epithelial cadherin (CD324) on epithelial cells, platelet/endothelial cell adhesion protein (PECAM-1/CD31) on endothelial cells, and Kit
Summary
Erythrocytes are the most abundant cells in circulation. They transport oxygen and have a half-life of around 22 d in mice and 120 d in humans. Constant production in the bone marrow (BM) is required to maintain the numbers of circulating RBCs. Erythropoiesis is the process whereby hematopoietic stem cells (HSCs) progressively differentiate into megakaryocyte/ erythrocyte progenitors (MEPs) and later into lineage-committed erythroid progenitors, immature burst-forming unit–erythroid cells (BFU-Es), and the more mature CFU-erythroid cells (CFU-Es). CFU-Es successively progress in differentiation through nucleated proerythroblast, basophilic, polychromatophilic, and orthochromatic stages, enucleation, and formation of RBCs. The distinct stages of erythroid differentiation are characterized by changes in surface expression of the progenitor marker Kit, of the transferrin receptor CD71, of the adhesion molecule CD44, and of the mature erythroid marker Ter119 (Kina et al, 2000; Aisen, 2004; Chen et al, 2009)
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