Abstract
BackgroundMacrophages have many functions in development and homeostasis as well as innate immunity. Recent studies in mammals suggest that cells arising in the yolk sac give rise to self-renewing macrophage populations that persist in adult tissues. Macrophage proliferation and differentiation is controlled by macrophage colony-stimulating factor (CSF1) and interleukin 34 (IL34), both agonists of the CSF1 receptor (CSF1R). In the current manuscript we describe the origin, function and regulation of macrophages, and the role of CSF1R signaling during embryonic development, using the chick as a model.ResultsBased upon RNA-sequencing comparison to bone marrow-derived macrophages grown in CSF1, we show that embryonic macrophages contribute around 2% of the total embryo RNA in day 7 chick embryos, and have similar gene expression profiles to bone marrow-derived macrophages. To explore the origins of embryonic and adult macrophages, we injected Hamburger-Hamilton stage 16 to 17 chick embryos with either yolk sac-derived blood cells, or bone marrow cells from EGFP+ donors. In both cases, the transferred cells gave rise to large numbers of EGFP+ tissue macrophages in the embryo. In the case of the yolk sac, these cells were not retained in hatched birds. Conversely, bone marrow EGFP+ cells gave rise to tissue macrophages in all organs of adult birds, and regenerated CSF1-responsive marrow macrophage progenitors. Surprisingly, they did not contribute to any other hematopoietic lineage. To explore the role of CSF1 further, we injected embryonic or hatchling CSF1R-reporter transgenic birds with a novel chicken CSF1-Fc conjugate. In both cases, the treatment produced a large increase in macrophage numbers in all tissues examined. There were no apparent adverse effects of chicken CSF1-Fc on embryonic or post-hatch development, but there was an unexpected increase in bone density in the treated hatchlings.ConclusionsThe data indicate that the yolk sac is not the major source of macrophages in adult birds, and that there is a macrophage-restricted, self-renewing progenitor cell in bone marrow. CSF1R is demonstrated to be limiting for macrophage development during development in ovo and post-hatch. The chicken provides a novel and tractable model to study the development of the mononuclear phagocyte system and CSF1R signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0121-9) contains supplementary material, which is available to authorized users.
Highlights
Macrophages have many functions in development and homeostasis as well as innate immunity
CSF1 receptor (CSF1R) mRNA was detected in embryos at around 2% of the level found in pure bone marrow-derived macrophages (BMDM)
Assuming similar levels of expression of CSF1R mRNA in tissue macrophages and BMDM, this would suggest that macrophages contribute around 2% of the total mRNA, which is consistent with their apparent abundance
Summary
Macrophages have many functions in development and homeostasis as well as innate immunity. In the current manuscript we describe the origin, function and regulation of macrophages, and the role of CSF1R signaling during embryonic development, using the chick as a model. The prevailing view that blood monocytes give rise to tissue macrophages in the steady state has been challenged by recent evidence in the mouse that phagocytic cells arising in the yolk sac can populate tissues during development and can be maintained through local proliferation [2,3]. Yolk sac-derived macrophages in the chick were shown to enter the developing central nervous system independently of vascularization [4]. Their origin was confirmed through the use of chick-quail yolk sac chimeras [5]. The inter-specific chimera system used did not permit full development, so there was no evidence from the chick system as to whether the yolk sac-derived cells were retained post-hatch
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