Many layers of embryonic hematopoiesis: new insights into B-cell ontogeny and the origin of hematopoietic stem cells

Abstract

In adult hematopoiesis, the hematopoietic stem cell (HSC) sits at the top of a hierarchy of hematopoietic progenitors responsible for generating the diverse repertoire of blood and immune cells. During embryonic development, however, the initial waves of hematopoiesis provide the first functioning blood cells of the developing embryo, such as primitive erythrocytes arising in the yolk sac, independently of HSCs. In the field of developmental immunology, it has been recognized that some components of the immune system, such as B-1a lymphocytes, are uniquely produced during the embryonic and neonatal period, suggesting a "layered" development of immunity. Several recent studies have shed new light on the developmental origin of the layered immune system, suggesting complex and sometimes multiple contributions to unique populations of innate-like immune cells from both fetal HSCs and earlier HSC-independent progenitors. In this review, we will attempt to synthesize these studies to provide an integrated model of developmental hematopoiesis and layered immunity that may offer new insights into the origin of HSCs.

Figure 1. HSC-independent waves of embryonic hematopoiesis contribute to self-maintaining, tissue-resident populations of innate-type immune cells in adult tissues

This includes microglia in the adult brain derived from primitive macrophage progenitors, tissue-resident macrophages (Kupffer cells, alveolar macrophages, and Langerhans cells) of the liver, lungs, and skin derived from erythromyeloid progenitors (EMP), some B-1a cells residing in the peritoneal and pleural cavities derived from embryonic B cell progenitors and/or lymphomyeloid progenitors (LMP), and some γδ T cells, including the subset of dendritic epidermal T cells (DETC), in skin and intestines derived from embryonic T cell progenitors and/or LMP. *It remains uncertain as to whether the earliest innate-type lymphoid wave is derived from the same lineage of hemogenic endothelium that later gives rise to HSC and/or from a distinct lineage of hemogenic endothelium (see Figure 2).

Figure 2. Models for the origin of multilineage progenitors that precede HSC during embryonic development

Acaulescent (HSC-independent) progenitors, as originally proposed by Nishikawa et al. (27), can either originate from a common lineage of hemogenic endothelial cells that have the capacity to give rise to HSC (A) or from distinct lineages of hemogenic endothelial cells that are heterogeneous in their hematopoietic potential (B). In the first model, hemogenic endothelial cells with multilineage potential undergo developmental maturation to acquire additional properties necessary to generate long-term HSC (LT-HSC). Prior to full maturation, a hemogenic endothelial cell that undergoes endothelial to hematopoietic transition (EHT) would give rise to HSC-independent hematopoietic progeny. In the second model, lineages of hemogenic endothelial cells with distinct hematopoietic potentials originate from mesoderm in separate temporal or spatial waves, similar to those giving rise to primitive progenitors and EMP, thus producing different populations of HSC-independent progenitors or HSC. LMP (lymphomyeloid progenitor), MPP (multipotent progenitor), ST-HSC (short-term HSC).