Drosophila as a model for the two myeloid blood cell systems in vertebrates

Abstract

Fish, mice, and humans rely on two coexisting myeloid blood cell systems. One is sustained by hematopoietic progenitor cells, which reside in specialized microenvironments (niches) in hematopoietic organs and give rise to cells of the monocyte lineage. The other system corresponds to the independent lineage of self-renewing tissue macrophages, which colonize organs during embryonic development and are maintained during later life by proliferation in local tissue microenvironments. However, little is known about the nature of these microenvironments and their regulation. Moreover, many vertebrate tissues contain a mix of both tissue-resident and monocyte-derived macrophages, posing a challenge to the study of lineage-specific regulatory mechanisms and function. This review highlights how research in the simple model organism Drosophila melanogaster can address many of these outstanding questions in the field. Drawing parallels between hematopoiesis in Drosophila and vertebrates, we illustrate the evolutionary conservation of the two myeloid systems across animal phyla. Much like vertebrates, Drosophila possesses a lineage of self-renewing tissue-resident macrophages, which we refer to as tissue hemocytes, as well as a "definitive" lineage of macrophages that derive from hematopoiesis in the progenitor-based lymph gland. We summarize key findings from Drosophila hematopoiesis that illustrate how local microenvironments, systemic signals, immune challenges, and nervous inputs regulate adaptive responses of tissue-resident macrophages and progenitor-based hematopoiesis to maximize fitness of the animal.

Figure 1. Ontogeny of blood cell lineages and regulation of hematopoiesis in Drosophila

(A) Self-renewing tissue macrophages, corresponding to Drosophila embryonic and larval hematopoiesis. Drosophila tissue-resident macrophages originate as prohemocyte progenitors (blue) in the head mesoderm at around embryonic stage 7. After four rounds of division, progenitors cease proliferation and differentiate into 600-700 macrophages (red) and a small number of crystal cells (orange). Crystal cells remain clustered around the proventriculus (‘cardia of the stomach’). Differentiating macrophages start migrating on routes from the anterior, and into the folded-over posterior end of the embryo (stage 11). By stage 15, macrophages have evenly populated the embryo. All macrophages remain quiescent (q) until the end of embryogenesis. At the transition to the larval stage, macrophages and crystal cells persist from the embryo. Macrophages colonize local microenvironments, in particular the segmentally repeated Hematopoietic Pockets (HPs), which also contain sensory neuron clusters (green). Localization to the HPs re-initiates macrophage proliferation, or ‘self-renewal’, which continues throughout larval life. Sensory neurons regulate the localization and expansion of tissue macrophages, raising the possibility that sensory stimuli from the environment and neuronal activity provide another layer of regulation. Macrophages are further regulated by systemic and/or local signals (green) stemming from immune challenges and signaling pathway activity. Many of these conditions cause premature mobilization of resident macrophages and induce differentiation into lamellocyte fate (not shown). Conversely, during normal larval development, resident tissue macrophages only gradually contribute to the pool of circulating macrophages in the hemolymph, and are released from their microenvironments at the onset of metamorphosis. Throughout larval development, crystal cells are found at locations similar to tissue macrophages but show only marginal increases in cell number. (B) Lymph Gland hematopoiesis. Prohemocytes are specified from hemangioblast precursors, which derive from the cardiogenic mesoderm of the embryo. Blood progenitors undergo four divisions in the embryo and continue to proliferate at a low rate until second larval instar. By the 3rd larval instar, blood cells in the Cortical Zone of the primary lobes (CZ) have differentiated into macrophages that expand further by proliferation, small numbers of crystal cells, and occasional lamellocytes. Progenitors in the Medullary Zone (MZ) have become quiescent (q). The proliferation and differentiation of LG blood cells is under the tight control of a wide range of signals, which arise from within the LG (PSC signals, CZ signals, MZ signals), and from systemic sources, such as neurotransmitters and growth factors from the brain, and nutritional compound levels. As development proceeds, virtually all blood cells of the lymph gland differentiate, and by 8h after puparium formation (APF), all lymph gland cells have been released into circulation. Adult flies appear devoid of significant hematopoietic activity, but carry over macrophages that persist from previous developmental stages. This places greater emphasis on the production and maintenance of blood cells in the embryo and larva, and explains the need for a multitude of regulatory mechanisms (signals and inductive tissues in green), which ensure adaptive responses of the blood cell pool during the sensitive period of larval development.