Drosophila macrophage self-renewal is regulated by transient expression of PDGF- and VEGF-related factor 2

Abstract

Macrophages are an ancient animal blood cell lineage critical for tissue homeostasis and defence against pathogens. Until recently, their numbers were thought to be sustained solely by specialised hematopoietic organs. It is now clear that many macrophages are instead replenished by self-renewal, yet the signals that regulate this remain poorly understood. In Drosophila melanogaster, macrophages (known as plasmatocytes) undergo a phase of rapid population expansion via self-renewal, making Drosophila an attractive model for revealing the signals and regulatory mechanisms involved. However, no central self-renewal pathway has been identified in Drosophila. Here, we investigated the PDGF-/VEGF-receptor pathway as a candidate for playing this role. Analysis of larvae deficient for each of the three PDGF-/VEGF-receptor ligands Pvf1-3 revealed Pvf2 as a major driver of macrophage self-renewal in Drosophila. We further found that only a small proportion of blood cells express Pvf2, and knockdown experiments implicate these cells as a major source of Pvf2 in self-renewal. Lineage tracing studies support the idea that Pvf2 expression in blood cells occurs transiently throughout the macrophage self-renewal period, and in response to an as yet unidentified cue. These data define the regulation of Pvf2 expression in blood cells as a central mechanism by which macrophage self-renewal is controlled. Given the strong parallels that exist between Drosophila and vertebrate macrophage systems, it is likely that similar mechanisms are at play across animal phyla.