Replacing the Brain’s Cleanup Machinery to Treat Neurological Disease


The Context: Microglia are resident immune cells of the brain that are constantly patrolling the central nervous system to eliminate dead or damaged cells. Defects in microglia can contribute to the development of neurodegenerative conditions such as Alzheimer’s. Scientists have been attempting to treat these diseases by introducing healthy microglia via bone marrow transplantation, but have run into challenges because the cells could not effectively penetrate the brain.

The Study: Scientists have pioneered a new and efficient method for microglia replacement in rodents using bone marrow stem cells and a chemical treatment to clear out existing microglia. Applying this approach to mice with a progressive neurodegenerative disease improved their motor behavior, reduced their brain inflammation, and extended their lifespan. The study, led by NYSCF – Robertson Stem Cell Investigator Alumnus and NYSCF – Robertson Stem Cell Prize Recipient Marius Wernig, MD, PhD, and including NYSCF – Druckenmiller Fellow Yongjin Yoo, PhD, from Stanford University, appears in Science Translational Medicine.

The Importance: These results point to a potential new and effective way to deliver therapeutics into the brain to treat multiple neurological conditions, and open the door to harnessing the therapeutic potential of these often overlooked cells. 

Microglia, the immune cells of the brain, are crucial for the proper function of the central nervous system. In normal conditions, they are constantly surveying the brain to gobble up pathogens and toxic molecules, but any defect in their function can also contribute to brain pathology. Dysfunctional microglia have in fact been implicated in many neurological disorders, such as Alzheimer’s and multiple sclerosis. 

Scientists have proposed that one way to ameliorate misbehaving microglia would be through a bone marrow transplant — a procedure in which healthy blood stem cells, which can produce all blood cell types including immune cells, are infused into the bloodstream of an individual to rebuild a functional immune system. Because microglia are the brain’s immune cells, such transplants could be a way to replace defective microglia with healthy ones. 

The attempts to achieve this have, however, not been successful. The brain is the best protected organ in the body, and most therapeutics cannot cross the blood-brain barrier — a physical barrier that prevents harmful substances from reaching the brain. Thus, finding means to penetrate this barrier would revolutionize the treatment of multiple brain diseases.

Helping Healthy Microglia Migrate to the Brain 

Dr. Wernig’s team had been trying to replace microglia through standard procedure of bone marrow transplantation without much success, so they sought an alternative approach: they infused bone marrow cells into mice previously treated with chemotherapy and, four weeks later, they injected them with a chemical that penetrates the brain and eliminates microglia. Doing so cleared out existing microglia and completely replenished the brain with donor bone marrow cells. What’s more, these cells turned into microglia-looking cells and remained stable in the brain for at least 6 months after transplantation. 

“That is exactly what we had tried for so many years to accomplish. And now, all of a sudden, we had a recipe,” Dr. Wernig told STAT News

The team then wanted to find out which specific cell type in the bone marrow was best for replacing  microglia. After infusing several different cell types, they found that hematopoietic stem cells — which can become any cell type in the blood – were the most effective at incorporating into the brain and replacing microglia.

They also saw that while bone marrow cells turned into microglia-resembling cells when they arrived in the brain, they behaved somewhat differently than standard microglia: their distinct ‘branched’ shape was less prominent, they gobbled up debris faster, and some genes were activated at higher levels. However, it is still unclear if all these differences have an impact on the brain’s function, and authors will explore that in future studies.

Toward Better Treatments for Brain Diseases

To see if their new microglia replacement method could treat disease, the team applied it to a mouse strain that develops a neurodegenerative disease caused by low levels of a protein called prosaposin. Remarkably, they found that mice transplanted with healthy cells not only improved their motor and balance abilities but also lived longer.

This is the first-ever demonstration that microglia replacement can improve disease symptoms, but it remains to be seen if it holds up in people. Since the current strategy includes a toxic chemotherapy treatment before transplantation, authors say that they first need to develop a safer strategy. Still, leveraging microglia as therapeutics could be a game changer for a wide range of brain diseases. 

Journal article:

Treatment of a genetic brain disease by CNS-wide microglia replacement
Yohei Shibuya, Kevin K. Kumar, Marius Marc-Daniel Mader, Yongjin Yoo, Luis Angel Ayala, Mu Zhou, Manuel Alexander Mohr, Gernot Neumayer, Ishan Kumar, Yamamotopaul Marcoux, Benjamin Liou, F. Chris Bennett, Hiromitsu Nakauchi, Ying Sunxiaoke Chen, Frank L. Heppner, Tony Wyss-Coray, Thomas C. Südhof, and Marius Wernig. Science Translational Medicine. March 2022. DOI:

Cover image: A section of a mouse brain showing replacement of microglia (green) after a bone marrow transplant. Credit: Yohei Shibuya, Stanford School of Medicine 

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