Tissue macrophage replacement in mice was systemic and long-lasting
In mice, donor macrophages, the resident immune cells of organs, populated the liver, kidneys, lungs, and spleen for nine months
On August 14, Advanced Science published an article on bone marrow transplantation in which descendants of donor cells replaced most tissue macrophages in four mouse organs. The authors measured how many cells remained after nine months and assessed how closely they had adopted the specialized features of each organ.
Many macrophages remain in tissues for years. They clear dead cells, contribute to tissue repair, and respond to infection. Microglia, the macrophages of the brain, belong to the same cell class. This approach was originally developed to replace microglia by first creating space for new cells and then transplanting bone marrow. PLX5622, which is used in the first step, also affects macrophages outside the brain. The new study therefore examined how this procedure affected the liver, kidneys, lungs, and spleen.
The mice received PLX5622 for two weeks. This compound blocks CSF1R signaling, which many macrophages require for survival. The animals were then prepared for transplantation with either whole-body irradiation at a dose of 9 Гр or a high dose of the chemotherapy drug busulfan. Donor bone marrow cells carried a green label, which allowed the researchers to identify their descendants in tissues. After nine months, donor-derived cells accounted for about 84% of liver macrophages, 99% of kidney macrophages, 92% of lung macrophages, and 99% of spleen macrophages.
Standard transplantation using the same irradiation or busulfan regimen produced a similar proportion of donor-derived cells. The authors attribute this result to the transplant conditioning itself. Irradiation and high-dose busulfan had already created many available niches in the tissues, so PLX5622 provided little additional improvement in engraftment.
The proportion of donor-derived cells shows how extensively they populated a tissue. Their specialization within the organ is a separate outcome. In the liver, donor-derived cells adopted part of the local program, but after nine months they still differed from Kupffer cells, the resident macrophages of the liver. Some features of mature Kupffer cells were less pronounced, and the DNA regions that regulate the expression of these genes remained organized differently. The organ environment altered the profile of the new cells, but their cellular origin still left a detectable signature.
The authors also assessed tissue structure, blood biochemistry, metabolism, behavior, and the response to the bacterial component LPS. These measurements indicated that the main organ functions and the innate immune response were preserved. The high proportion of donor-derived cells and the extent of their similarity to the original tissue macrophages describe different aspects of replacement. This mouse study measured both outcomes: whether the new cells remained in the tissues and how much of the local specialization they acquired.