Fetal liver myelopoiesis occurs through distinct, prospectively isolatable progenitor subsets

Abstract

Hematopoietic fate maps in the developing mouse embryo remain imprecise. Definitive, adult-type hematopoiesis first appears in the fetal liver, then progresses to the spleen and bone marrow. Clonogenic common lymphoid progenitors and clonogenic common myeloid progenitors (CMPs) in adult mouse bone marrow that give rise to all lymphoid and myeloid lineages, respectively, have recently been identified. Here it is shown that myelopoiesis in the fetal liver similarly proceeds through a CMP equivalent. Fetal liver CMPs give rise to megakaryocyte-erythrocyte-restricted progenitors (MEPs) and granulocyte-monocyte-restricted progenitors (GMPs) that can also be prospectively isolated by cell surface phenotype. MEPs and GMPs generate mutually exclusive cell types in clonogenic colony assays and in transplantation experiments, suggesting that the lineage restriction observed within each progenitor subset is absolute under normal conditions. Purified progenitor populations were used to analyze expression profiles of various hematopoiesis-related genes. Expression patterns closely matched those of the adult counterpart populations. These results suggest that adult hematopoietic hierarchies are determined early in the development of the definitive immune system and suggest that the molecular mechanisms underlying cell fate decisions within the myeloerythroid lineages are conserved from embryo to adult. IntroductionThe genesis of the mammalian immune system has best been studied in the mouse, where hematopoiesis occurs through a stepwise process that begins in the yolk sac (YS) on embryonic day 7 (E7). 1 Only primitive erythropoiesis is evident in this organ, which is characterized by the production of erythrocytes with unextruded nuclei and expression of embryonic globin genes. 2 Hematopoiesis then appears in the aorta-gonad-mesonephros (AGM) region of the para-aortic splanchnopleura in the developing mouse embryo from E8 to E10, after which the fetal liver (FL) becomes the major site of embryonic blood production from approximately E12 to birth. 2 Although culture and transplantation experiments have shown that both the YS 1,3 and AGM 4,5 regions contain multipotent hematopoietic stem cells (HSCs), definitive, multilineage hematopoiesis does not occur until the FL becomes the predominant hematopoietic organ. 2 This suggests that environmental cues may restrict and specify the cell fate determinations of HSCs. Cellular transplants of identical hematopoietic progenitors clearly show that differing environments can lead to different cell fates, 1,3,6 suggesting that local niches specify lineage determination. Alternatively, hematopoietic precursors may be genetically distinct among the shifting sites of hematopoiesis in the developing immune system.HSCs capable of long-term, multilineage reconstitution are prospectively isolatable from murine FL using cell surface marker profiles roughly equivalent to those of adult HSCs. 7 FL-HSCs, however, show several phenotypic and functional differences when compared to their adult counte...

E2F4 Modulates Differentiation and Gene Expression in Hematopoietic Progenitor Cells during Commitment to the Lymphoid Lineage

“…In this experiment, we use the term "CLP-like" to define these cells phenotypically. We also identified a subset of early myeloid cells that were Lin Ϫ , sca-1 Ϫ , and c-kit ϩ ; these cells were further subdivided based on CD16 and CD34 expression into subsets corresponding to CMP, granulocyte-macrophage progenitors (GMP), and megakaryocyte-erythroid progenitors (MEP) (21). Because our experiments use the surface phenotype to define these subsets of cells, we use the operation terms GMP-like, CMP-like, and MEP-like.…”

Prospective isolation of human clonogenic common myeloid progenitors

“…It is unclear whether the minor B cell progeny is derived from contaminants of lymphoid precursors among a high number of CMPs transplanted or whether putative bipotent B cell͞myeloid progenitors share their surface phenotype with CMPs. It shall be important to clarify this issue by future studies, because minor B cell potentials were observed similarly in both fetal and adult murine CMPs (2,26).…”

Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation

“…This was confirmed by flow cytometric analysis of the different myeloid progenitor subsets. 27 Both common myeloid progenitors (CMPs; Fc␥R lo CD34 ϩ ) and granulocyte-monocyteprogenitors (GMPs; Fc␥R hi CD34 ϩ ) frequencies in Wnt3a Ϫ/Ϫ FLs were severely reduced. Megakaryocyte-erythrocyte progenitors (MEPs; Fc␥R lo CD34 Ϫ ) were not affected ( Figure 4F,G).…”