Embryonic Origins of the Hematopoietic System: Hierarchies and Heterogeneity

Abstract

The hierarchical framework of the adult blood system as we know it from current medical and hematology textbooks, displays a linear branching network of dividing and differentiated cells essential for the growth and maintenance of the healthy organism. This view of the hierarchy has evolved over the last 75 years. An amazing increase in cellular complexity has been realized; however, innovative single-cell technologies continue to uncover essential cell types and functions in animal models and the human blood system. The most potent cell of the hematopoietic hierarchy is the hematopoietic stem cell. Stem cells for adult tissues are the long-lived self-renewing cellular component, which ensure that differentiated tissue-specific cells are maintained and replaced through the entire adult lifespan. Although much blood research is focused on hematopoietic tissue homeostasis, replacement and regeneration during adult life, embryological studies have widened and enriched our understanding of additional developmental hierarchies and interacting cells of this life-sustaining tissue. Here, we review the current state of knowledge of the hierarchical organization and the vast heterogeneity of the hematopoietic system from embryonic to adult stages.

Figure 1.

Timeline of major advances in hematology and hematopoietic development. Our understanding of hematopoietic hierarchies is shaped by major breakthroughs in the fields of developmental and adult hematopoiesis. These breakthroughs revealing the generation and organization of the hematopoietic system (from over a century ago to the present time) are summarized for the distinct embryonic hierarchies found in the YS, major vasculature (aorta, umbilical/vitelline arteries), and fetal liver (top panel). Breakthrough findings from the BM are summarized for the adult hematopoietic hierarchy (bottom panel). The foundations for the cellular basis of blood generation and the discovery of the HSC as the founder cell for the adult hierarchy led to the use of these self-renewing, multipotent cells in clinical transplantation therapies for hematopoietic disorders. Clonal transplantation analyses revealed the heterogeneity of HSCs (indicated by lighter-colored panels) in their lineage differentiation bias and longevity. Advancements in cellular (phenotypic, functional) and molecular (transcriptomics, regulatory networks) analyses led to further discoveries. See review for details and references. AGM = aorta-gonad-mesonephros; BM = bone marrow; CFU-S = colony-forming unit-spleen; EHT = endothelial-to-hematopoietic transition; HSC = hematopoietic stem cell; IAHC = intra-aortic hematopoietic clusters; ST-/LT- = short-term/long-term; YS = yolk sac.

Figure 2.

Overview of the developmental and adult hierarchies. (A) Embryonic hematopoiesis occurs in 3 waves. The first (primitive) wave starts at mouse embryonic day (E)7.5 in the YS blood islands with the formation of primitive erythrocytes, megakaryocytes and macrophages. The second (pro-definitive) wave starts just before the onset of circulation at E8.25 with the production of erythroid-myeloid progenitors from the YS. From around E9.0/9.5 these are also found in the blood, pSp, and chorio-allantois/placenta. From around E8.5/9.0, lymphoid potential from LMPPs is detected, slightly earlier in the pSp than YS. At E9.5, a MPP and CFU-S emerge in the YS and AGM region. In the third/adult-definitive wave (E10.5), the first long-term multilineage adult-repopulation HSCs are generated in the AGM. Slightly later, HSCs are found in the umbilical and vitelline arteries, placenta, YS, and head. They will next migrate to and expand in the fetal liver, together with EMPs. Schematic drawings show E7.5, E8.25 and E10.5 embryos with sites of hematopoietic activity colored in red. (B) Adult hematopoietic hierarchy with bifurcating differentiation pathways from the most potent long-term (LT-)HSCs to progenitor intermediates (arrows) and mature cell lineages (not shown; dashed arrows). Advances in single-cell transcriptomics have now led to a hematopoietic tree that depicts differentiation more like a continuum (not shown) rather than a highly-grouped hierarchy with fixed intermediate steps. (C) Representation of morphological and cell-specific marker changes during EHT in the midgestation mouse aorta. Through the expression of pivotal hematopoietic transcription factors (Runx1, Gata2), the HEC fraction (light red) of the endothelium, undergoes EHT to form IAHCs that gain hematopoietic characteristics (dark red) as they advance away from the endothelium. Once required/fully matured, the HSPCs will detach from IAHCs and enter circulation. Onset of expression of specific genes and markers is indicated above the schematic of the different EHT stages. AGM = aorta-gonad-mesonephros; CFU-S = spleen colony-forming unit; CLP = common lymphoid progenitor; CMP = common myeloid progenitor; EHT = endothelial-to-hematopoietic transition; GMP = granulocyte-monocyte progenitor; HSCs = hematopoietic stem cells; IAHCs = intra-aortic hematopoietic clusters; LMPPs = lymphoid-primed multipotent progenitors; MEP = megakaryocyte-erythrocyte progenitor; MLP = multilymphoid progenitor; MPP = multipotent progenitor; pSp = para-aortic splanchnopleura; ST = short-term; YS = yolk sac.