Exchange of brain microglia treats neurological diseases in mice


FFrom anemia to leukemia, unhealthy cells can result in unhealthy people, but replacing these cells can help patients. What if the same were true for some of the world’s most devastating neurological diseases?

A new study published Wednesday in Science Translational Medicine raises the tantalizing possibility that researchers may one day replace microglia — cells that form a traveling cleaning crew that scours the brain for signs of infection and damage. A team led by Stanford scientists has discovered that microglia can be replaced in mice by an infusion of stem cells as part of a bone marrow transplant. This allowed mice with a neurodegenerative disease to live longer and move around more normally.

The study’s authors and observers say this is the first-ever study to report that replacing microglia can help treat a disease. But there’s no guarantee that the discovery will stick with people. And the researchers say they would first like to modify the procedure so that it is less toxic.

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Yet the results offer hope that isolating a person’s blood stem cells, correcting their genetic errors, and reintroducing those cells could remedy microglia defects in a wide range of brain diseases, from neurological diseases rare in Alzheimer’s disease.

“Essentially any genetic disease that affects microglia would be a fantastic target,” said Marius Wernig, a Stanford stem cell researcher and lead author of the study. “Because then you know you’ve solved the problem.”

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Scientists’ understanding of what microglia do — and why they matter — has changed dramatically over the years. These spindly cells were once dwarfed by neurons, but researchers now know they are the brain’s resident immune cells, a kind of local police that gobble up dead, abandoned cells.

Microglia also profoundly shape one of the brain’s most fundamental processes: the creation of memories, which are wired as connections between neurons. These cells can literally eat up these connections, influencing what we remember and how we learn.

Several DNA mutations linked to neurological diseases are found in genes associated with microglia. And biotech companies have taken notice. Vigil Neurosciences of Cambridge, Mass., is working on a microglia-based treatment for a rare neurodegenerative disease called adult leukoencephalopathy. And Bay Area Biotechnology Alector is developing three different drugs for Alzheimer’s disease that target microglia.

In the current study, Wernig’s team tested what they hope will be a more direct and long-lasting solution: completely replacing the defective microglia. It was not easy. This is because although the standard way to replace immune cells is through a bone marrow transplant, the procedure does not effectively replace microglia, which do not normally rely on bone marrow cells to maintain their own numbers in the brain. .

The authors therefore tried a different approach. Shortly after the transplant, they injected mice with a chemical that blocks a key pathway for microglia to grow and survive. This removed the existing microglia and these cells were quickly replenished with transplanted cells. Under a microscope, the cell mat baggers, marked with a protein that made them glow green, looked like a constellation flickering across the brain.

“When I first saw these images, I was blown away,” said Wernig, who has spent more than 20 years struggling to move cells through the brain. “That’s exactly what we’ve been trying to accomplish for so many years. And now, all of a sudden, we had a recipe.

Other researchers have successfully used a similar recipe, including a French group who published their findings in natural medicine in February. Wernig suspects that the combination of pre-transplant chemotherapy and microglia scavenging allows transplanted cells to enter the brain and ensures they will have room to make a new home when they arrive.

The authors tinkered with infusing different cell types to see which was best for replacing microglia. They found that hematopoietic stem cells – which can grow into virtually any type of blood cell – were the best grafting material.

They also found that although the newcomers to the brain looked and acted like microglia, they weren’t quite identical to the cells they were replacing. In some cases, they were more likely to munch on cellular debris than standard microglia. And there were subtle differences in how the transplanted cells and the native microglia turned on various genes.

The team then tried to do something no one had done before: show that exchanging microglia could help treat the disease. To do this, the scientists worked with a strain of mice that develops a neurodegenerative disease triggered by low levels of a protein called prosaposin in several cell types, including microglia. Replacing the microglia in these mice with cells from mice that lacked a key mutation allowed the animals to have more normal balance and movement. The mice also survived longer.

“Certainly interesting and possibly potentially translationally relevant,” said Susan Kaech, an immunologist at the Salk Institute who studies microglia and was not involved in the study.

She added that she was surprised the authors didn’t use an Alzheimer’s mouse model because there are strains of mice that carry disease-associated genes in microglia. The model used by the authors is not a perfect replica of a human neurodegenerative disease, but it is used to study some aspects of Gaucher disease, a rare metabolic disorder that can trigger neurological symptoms.

Wernig’s team now plans to test whether their findings are valid in monkeys. They also wonder how to make the transplant protocol less toxic. Treating a patient with chemotherapy or radiation therapy before a bone marrow transplant is common practice. But in this case, the researchers are trying to replace brain cells, not bone marrow, so they hope to find another solution with fewer side effects. It’s also unclear whether the differences the science team found between the replacement cells and native microglia are significant, Wernig adds, and, if so, whether it’s helpful or harmful.

“Bottom line, it has to be tested,” he said.

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