The immune system is made up of specialized cells and proteins that help defend the body from pathogens and cancer. Most of the time, the immune system performs its job remarkably well. However, in some situations, the immune system doesn't work well enough or works in overdrive, causing disease.
Immune system cells are derived from stem cells located in bone marrow. When a specific type of immune cell becomes cancerous or genetic mutations make immune cells work improperly, the best treatment may be to replace the patient's bone marrow with normal bone marrow that produces normal immune cells.
Traditional bone marrow transplantation (tBMT) is a lifesaving treatment in many cases, but the technique isn't perfect: donor immune cells do not engraft into the central nervous system (CNS) well. In particular, macrophages (white blood cells that digest harmful pathogens, dead cells and waste) and specialized CNS macrophages called microglia demonstrate minimal replacement in the brain under normal conditions.
In 2020, researchers from Fudan University first developed a robust and reproducible strategy to achieve efficient engraftment of microglial cells in the CNS, called microglia replacement by bone marrow transplantation (Mr BMT) (DOI: 10.1016/j.celrep.2020.108041). A few years later, this group first reported the clinical efficacy of microglia replacement in a fatal brain disease named adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) (DOI: 10.1126/science.adr1015; preprint DOI: 10.1101/2024.06.11.598496), which is caused by microglial dysfunction. This team recently performed a new study to assess the engraftment of macrophages into organs outside of the brain.
The team published their paper, "Mr BMT achieves systemic macrophage replacement with preservation of tissue homeostasis," on August 14 in the journal Advanced Science (DOI: 10.1002/advs.202519669).
"In 2020, our group achieved efficient strategies of microglia replacement in mice for the first time. Mr BMT is one of our three techniques, and it has become the most commonly used and successful strategy for microglia replacement. In addition to CNS microglia, Mr BMT can also replace macrophages in peripheral organs. As an increasingly recognized and promising strategy for brain disease treatment, it is important to evaluate the long-term safety and biological effects of Mr BMT on peripheral organs," said Yanxia Rao, associate professor at Fudan University and senior author of the research study.
The Mr BMT technique first depletes microglia in the CNS before transplanting donor bone marrow cells (BMCs) using PLX5622, a molecule that blocks the action of colony-stimulating factor 1 receptor (CSF1R), a protein that sits on the surface of primarily brain immune cells and controls their survival. By blocking this receptor with PLX5622, most of the existing microglia in the CNS is depleted prior to bone marrow transplant, creating empty niches for new bone marrow transplant cells to reside. Importantly however, the team needed to establish the safety of the Mr BMT technique, as it also replaces macrophages in the liver, kidney, spleen and lung.
The team observed good replacement of macrophages in mouse liver, kidney, lung and spleen, with similar engraftment rates for both tBMT and Mr BMT. The durability of macrophage replacement also lasted at least 9 months in the study, and importantly, Mr BMT preserves the innate immune response in engrafted tissues after exposure to lipopolysaccharide (LPS, a large molecule found in the outer membrane of Gram-negative bacteria like E. coli and Salmonella).
Analysis of the transcriptome, or gene mRNA expression, of transplanted Mr BMT macrophages also revealed that administering PLX5622 in the course of the Mr BMT technique does delay the development of macrophage characteristics in donor-derived (transplanted) cells in the first month after transplant. However, macrophage-signature gene expression recovered over time in Mr BMT macrophages to reflect the macrophage gene expression in mice that had not undergone bone marrow transplant. The team presumes that this time allowed the engrafted cells to adapt to the local tissue environment.
"Mr BMT establishes durable systemic macrophage replacement in peripheral organs while preserving overt tissue homeostasis," said Bo Peng, distinguished professor at Fudan University and a senior author of the research paper. "Although replaced macrophages remained kind of distinct from the original tissue-resident macrophages, these molecular differences did not result in overt functional impairment. The tissue integrity, overall metabolic state and core biological functions were largely preserved following transplantation."
This latest study provides tangible evidence of the safety of the Mr BMT technique in mice, which researchers hope will translate to safe, effective disease treatment in humans.
"Due to the dual replacement of macrophages and microglia in both the CNS and peripheral compartments, Mr BMT and other microglia replacement strategies can be applied to simultaneously treat disease with CNS and peripheral pathologies, expanding the therapeutic potential of microglia replacement beyond the CNS" said Rao.
This work was supported by Brain Science and Brain-like Intelligence Technology–National Science and Technology Major Project (2022ZD0204700, 2022ZD0207200); National Natural Science Foundation of China (32571128, 323B2030, 325B2039); Fellowship of China National
Postdoctoral Program for Innovative Talents (BX20250132); Fellowship of China Postdoctoral Science Foundation (2025M782569); Shanghai Pilot Program for Basic Research (21TQ014), Changping Laboratory (2025B-07-18) and Lin Gang Laboratory (LGL-8998-02).
