Delivering Microglia-Like Cells to the Brain to Break Down Amyloid-β
The future of cell therapies might prove to be one in which transplants are largely done away with. Cell engineers will instead issue a carefully controlled set of signals that cause the body to generate the desired additional population of cells, move those cells to where they are needed, and then put them to work in a specific way. We stand a long way removed from the full realization of this sort of treatment, not least because the signaling environment of most tissues is still largely terra incognita when it comes to the fine details, but the research noted here is certainly a start along that road.
For brain microglia struggling to keep amyloid plaques under control, help could be on the way. Researchers have identified an antibody that triggers mouse bone marrow myeloid progenitors to become phagocytic microglia-like cells, which then make their way to the brain. In a mouse model of Alzheimer's disease (AD), the cells clustered around amyloid deposits and reduced plaque load.
The findings grew out of a problem seen with stem-cell therapies - it's not enough to generate the desired type of cell; the cells also must be directed to where they are needed. "After embryogenesis, the 'go there' part is shut down. Controlling migration is the other half of stem-cell therapy." To address that, researchers devised a screen for antibodies that induce stem cells to not only differentiate but also migrate to different tissues. After expressing antibodies on bone-marrow stem cells, researchers put those cells in mice and looked for the ones that gained the ability to migrate to the brain or other tissues. "In a normal selection, you look at a cell population and find something that's different. In this migration-based selection, the cells self-purify because they run away from the bone marrow, and take up residence in other tissues."
Researchers started with a lentivirus expression library comprising 100 million different single-chain antibody genes. They infected freshly isolated mouse bone-marrow cells with the library, then transplanted the entire batch of infected cells into mice whose own bone marrow had been destroyed by whole-body irradiation. After a week, they used PCR to detect traces of the antibody genes in different tissues. Of 60 different genes detected, they found one, dubbed B1, six times in brain tissue from different mice, and never in spleen, liver, or heart.
To ask if the microglia-like cells attack amyloid in vivo, the researchers repeated their transplantation experiments using APP/PS1 mice. They infused B1-transduced bone marrow cells into irradiated eight-week-old animals, and then waited. After six months, the B1 mice harbored approximately 60 percent less amyloid in their brains than animals transplanted with control bone marrow. The animals also had more microglia and fewer astrocytes than irradiated controls. Does B1 treatment induce bona fide microglia and if so, what type? This is difficult to evaluate. "I don't think these cells are the real deal, but I don't care. If, as claimed in the study, this antibody induces a type of cell that can migrate to plaque in non-irradiated mice, that's important. If this is associated with plaque removal, that's huge. Whether the cells become microglia is not as important."
The last quote clearly shows that he is more an engineer than an scientist. Good to see that!
These microglia could cause inflammation.