When they were first discovered by the Russian scientist Élie Metchnikoff in 1884, macrophages were thought to be important for engulfing foreign particles and protecting the body from infection. In the years since then, scientists have found that macrophages also play an unexpected role in tissue development and homeostasis, with their effect depending on the specific tissue they reside in.
Ten years ago, Florent Ginhoux, a Senior Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN), showed that macrophages arise from two separate and distinct sources—during embryonic development and from adult bone marrow respectively—rather than solely from adult blood cells called monocytes as previously thought. However, this study was conducted in mice and it was not known if human macrophages followed the same developmental process.
To find out if macrophages followed the same developmental path in humans as in mice, Ginhoux and his collaborators at Jinan University, China, mapped the developmental trajectory of macrophages in early human embryos. The researchers analyzed tissue from the yolk sac, head, liver and lungs of embryos at various stages of early development and used state of the art single-cell transcriptomics techniques to identify and group populations of macrophages.
The researchers found that the earliest macrophages originate from the yolk sac in two waves: the earlier wave contributes to a monocyte-independent macrophage population and the later wave to fetal monocyte-derived macrophages.
“What surprised us the most was the striking similarity between human and mouse embryonic hematopoietic development,” said Christopher Lee, an A*STAR scholar at Ginhoux’s lab and co-first author of the study. “This means that the fundamental process of development and the immune system are largely conserved, and animal work will continue to be an indispensable part of how we understand human biology,” added Ginhoux.
The researchers also looked at the fate of macrophages in the different anatomical sites by comparing their data in embryos with available data from adults. They found differences in the extent of specialization of macrophages in the embryo head and liver compared to the lung, suggesting that the signals needed for the specialization of cells in the lungs were missing in this early stage of development.
At the moment, many systems used to study human macrophages assume that they all come from blood monocytes. “Our discovery has shown that this may not be true, and we will now have to take into account the origin of macrophages when trying to study them,” Ginhoux said. His team is now developing a model system that can account for the differing origins of some tissue-resident macrophages, which could have implications for understanding the role they play particularly in solid tumors where macrophages are thought to drive tumor progression.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).