Embryonic Macrophages Influence Blood Stem Cell Formation

Scientists at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena have discovered a previously unknown function of immune cells in the bone marrow. Embryonic macrophages – specialized phagocytes of the immune system – influence the formation of blood stem cells and thus the lifelong production of blood cells. They play a crucial role in regulating the size of the hematopoietic stem cell pool, which is essential for the continuous production of blood cells and the maintenance of a healthy immune system.

Our immune system is subject to constant renewal, as immune and blood cells have a limited lifespan and therefore must be constantly replaced. This is ensured by blood-forming stem cells located in the bone marrow. The process of blood cell formation is very important for maintaining a functional immune system and therefore for health in old age. For the process of blood cell formation to function smoothly, a special environment is necessary: ​​the hematopoietic niche, which consists of many supporting cells. How this niche forms during development is largely unknown.

A recent study by the research group led by Prof. Claudia Waskow at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena discovered that phagocytes called macrophages, which develop before birth (embryonic development), play a key role in this process. These cells regulate the number of blood stem cells in the bone marrow and thus play a crucial role in lifelong blood cell production. The research results have now been published in the renowned journal "Nature Communications" (DOI: 10.1038/s41467-025-59059-9).

Macrophages - Heterogeneous stem cell population

The research team was able to show that there are two distinct groups of macrophages in the bone marrow: one with an embryonic origin, and one that develops from other stem cells after birth. "The macrophage cell population is heterogeneous and, depending on age, is composed of macrophages of different origins, so that they either originate from embryonic development or develop with increasing age in adulthood," explains Prof. Waskow, head of the "Immunology of Aging" research group at the FLI.

Embryonic macrophages regulate stem cell number

Despite their similar morphology (external appearance), macrophages differ significantly in their function. "Embryonic macrophages, in particular, are essential for the correct number of blood stem cells in the bone marrow, but are not required for their initial formation in the embryo," emphasizes Dr. Gülce Perçin, the study's lead author. "If these macrophages are missing, the number of blood stem cells is reduced and there are fewer precursor cells for new blood cells. They thus influence the body's ability to produce new blood cells throughout life."

Migration of hematopoietic stem cells depends on embryonic macrophages

But how do embryonic macrophages do this? Their absence impacts the migration of blood-forming stem cells into the bone marrow. The stem cells develop in other locations in the embryo and migrate into the bone marrow around birth, where they then remain for life. The stem cells find their "destination" through chemical signals from the bone marrow – comparable to a special "smell" – which the stem cells recognize and thus know where they are needed. Mesenchymal stromal cells, which occur in the niche environment, are able to secrete these important signals for stem cells. However, the number of these specialized stromal cells and the production of the signals are coordinated by the macrophages of embryonic origin residing in the bone marrow. If the embryonic macrophages are missing, the process of blood stem cell migration no longer functions optimally.

New insights into blood formation and immune defense

"Our results illustrate the complexity of the interactions during the establishment of hematopoiesis activity in the bone marrow and highlight the importance of ontogeny, i.e., the origin of macrophages. They underscore that bone marrow macrophages are not just simple immune cells, but actively regulate the conditions for healthy hematopoiesis," the study authors summarize. "If we succeed in further understanding the role of embryonic macrophages, this would not only have far-reaching implications for research into age-related diseases. Identifying the regulatory mechanisms underlying the establishment and maintenance of adult hematopoiesis could also open up new therapeutic approaches to promote health in old age."

Reference: Perçin G, Riege K, Fröbel J, et al. Embryonic macrophages orchestrate niche cell homeostasis for the establishment of the definitive hematopoietic stem cell pool. Nat Commun. 2025;16(1):4428. doi: 10.1038/s41467-025-59059-9

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