Hematopoiesis: A Layered Organization Across Chordate Species

Abstract

The identification of distinct waves of progenitors during development, each corresponding to a specific time, space, and function, provided the basis for the concept of a "layered" organization in development. The concept of a layered hematopoiesis was established by classical embryology studies in birds and amphibians. Recent progress in generating reliable lineage tracing models together with transcriptional and proteomic analyses in single cells revealed that, also in mammals, the hematopoietic system evolves in successive waves of progenitors with distinct properties and fate. During embryogenesis, sequential waves of hematopoietic progenitors emerge at different anatomic sites, generating specific cell types with distinct functions and tissue homing capacities. The first progenitors originate in the yolk sac before the emergence of hematopoietic stem cells, some giving rise to progenies that persist throughout life. Hematopoietic stem cell-derived cells that protect organisms against environmental pathogens follow the same sequential strategy, with subsets of lymphoid cells being only produced during embryonic development. Growing evidence indicates that fetal immune cells contribute to the proper development of the organs they seed and later ensure life-long tissue homeostasis and immune protection. They include macrophages, mast cells, some γδ T cells, B-1 B cells, and innate lymphoid cells, which have "non-redundant" functions, and early perturbations in their development or function affect immunity in the adult. These observations challenged the view that all hematopoietic cells found in the adult result from constant and monotonous production from bone marrow-resident hematopoietic stem cells. In this review, we evaluate evidence for a layered hematopoietic system across species. We discuss mechanisms and selective pressures leading to the temporal generation of different cell types. We elaborate on the consequences of disturbing fetal immune cells on tissue homeostasis and immune development later in life.

Keywords: embryo; evo devo biology; hematopoieisis; layered; lymphopoieis.

FIGURE 1

Phylogenetic tree of chordates showing the evolutionary relationships of the hematopoietic system. A phylogeny representing Cephalochordata to Amniota, illustrating the development of a layered hematopoietic system with (i) yolk sac (YS) or extra-embryonic primitive hematopoietic cell generation in blue, (ii) YS definitive hematopoietic cell generation in orange, and (iii) intra-embryonic definitive hematopoiesis in green. Osteichthyes (which include zebrafish, axolotl, Xenopus, birds, mice, and humans) were the first where the distinct origins of hematopoietic cells have been demonstrated. Lack of information on specific processes are represented with a question mark.

FIGURE 2

Embryonic origin of the hematopoietic system. (A) Timeline of hematopoietic development in zebrafish. In zebrafish, primitive hematopoiesis occurs in the RBI and ICM region generating primitive macrophages and erythrocytes, respectively. The CHT, consisting of the CA (the continuation of the DA as it enters the tail), CV, and an endothelial network in between, the CVP, hosts a niche for HSC expansion and differentiation, reaching a peak at around E6. (B) In chicken, primitive hematopoiesis at E1.5 occurs in the YS blood islands. IAHCs are first detected at E2.25, reach a peak at E3, and gradually decrease, being residual at E5.5. PAF cells are detected at E2.5, rapidly surpassing the number of HIAC and last until around E9. (C) In Xenopus, the first hematopoietic site is the VBI (YS equivalent). Subsequent generation occurs after progenitor cells from the DLP migrate to the midline where they coalesce to give rise to the dorsal aorta (AGM). Cells from the two waves colonize the liver, which is the definitive site of hematopoiesis in both larval and adult stages. Xenopus were staged according to Nieuwkoop and Faber. See http://www.xenbase.org/anatomy/alldev.do for equivalences to dpf. AGM, aorta-gonad-mesonephros; aVBI, anterior VBI; BM, bone marrow; CA, caudal artery; CHT, caudal hematopoietic tissue; CVP, caudal vein plexus; DA, dorsal aorta; ICM, intermediate cell mass; FL, fetal liver; PAF, para-aortic foci; PBI, posterior blood island; PLM, posterior-lateral mesoderm; pVBI, posterior VBI; plVBI, posterior-lateral VBI; RBI, rostral blood islands; YS, yolk sac; VBI, ventral blood island.

FIGURE 3

HSC emergence at the dorsal aorta in mice, chicken, and zebrafish. Intra-embryonic hematopoietic clusters (IAHCs) containing newly formed HSCs in birds and in mammals. IAHC originate from PAF in chicken and sub-aortic patches in mice. Contrary to mammals and birds, IAHCs are not observed in zebrafish and newly formed HSCs do not enter directly into circulation. CV, caudal vein; D, dorsal; DA, dorsal aorta; V, ventral; PAF, para-aortic foci.

FIGURE 4

Tissue-resident immune cells are mosaic of cells derived at different developmental stages. Different hematopoietic progenitors are generated during development, some of which contribute to the adult tissue-resident immune cell compartment diversity. It is still unknown which functions these cells play during development and whether they persist in adulthood. ILCP, ILC progenitor; My, myeloid cells; NKT, NK T cells; MAIT, mucosal-associated invariant T cells.

FIGURE 5

The fetal thymus is colonized by two successive waves of hematopoietic progenitors. Scheme of the timeline of thymus colonization in the mouse. Area of the Gaussian curves is proportional to the number of progenitors in each wave. The first wave generates few cells whereas the second expands before differentiation but lacks the capacity to generate LTi and Vγ5⁺ T cells.