Contributions of Embryonic HSC-Independent Hematopoiesis to Organogenesis and the Adult Hematopoietic System

Abstract

During ontogeny, the establishment of the hematopoietic system takes place in several phases, separated both in time and location. The process is initiated extra-embryonically in the yolk sac (YS) and concludes in the main arteries of the embryo with the formation of hematopoietic stem cells (HSC). Initially, it was thought that HSC-independent hematopoietic YS cells were transient, and only required to bridge the gap to HSC activity. However, in recent years it has become clear that these cells also contribute to embryonic organogenesis, including the emergence of HSCs. Furthermore, some of these early HSC-independent YS cells persist into adulthood as distinct hematopoietic populations. These previously unrecognized abilities of embryonic HSC-independent hematopoietic cells constitute a new field of interest. Here, we aim to provide a succinct overview of the current knowledge regarding the contribution of YS-derived hematopoietic cells to the development of the embryo and the adult hematopoietic system.

Keywords: HSC-independent hematopoiesis; embryonic hematopoiesis; hematopoietic waves; lineage tracing; macrophage; organogenesis; yolk sac.

FIGURE 1

The hematopoietic system is established in developmental waves that differentially contribute to embryonic organogenesis and the adult hematopoietic system. (A) Schematic representing the timing and embryonic sites of hematopoietic activity during mouse development. The three waves of hematopoiesis are represented in Blue (wave 1: primitive erythrocytes, megakaryocytes, macrophages and Early EMP), Orange (wave 2: Late EMP and LMP) and Green (wave 3: HSPC). Wave 1 is known as the primitive wave while waves 2 and 3 constitute the definitive waves of hematopoiesis. Waves 1 and 2 which do not generate HSCs originate in the Yolk Sac while wave 3, which generates the HSPCs, is initiated in the AGM region of the embryo proper. Cells from both waves 2 and 3 can colonize the fetal liver where they can mature and expand before moving to their final destination. (B) (Left) HSC-independent macrophages which originate from the first two hematopoietic waves have been shown to play important roles during embryonic development of several tissues and organs. (Right) In addition to the wave 3 (Green) HSC-derived hematopoietic cells, the HSC-independent hematopoietic cells generated during wave 1 (Blue) and 2 (Orange) persist, to varying degrees, in adult tissues and organs. Waves that contribute most of the hematopoietic cells are depicted in bold and waves for which the contribution increases overtime are circled. Blue: hematopoietic wave 1 (primitive), Orange: hematopoietic wave 2 (Late-EMP/LMP), Green: hematopoietic wave 3 (HSC). E, embryonic day; Mφ, macrophage; HSC, hematopoietic stem cell; EMP, erythroid–myeloid progenitor; LMP, lymphoid–myeloid progenitor; HSPC, hematopoietic stem and progenitor cell; P-Sp, para-aortic splanchnopleura; AGM, aorta-gonad-mesonephros.