Researchers at Fudan University in Shanghai, China have developed three different techniques that successfully replace almost all malfunctioning microglia - each technique with its own advantage in application.
Specialised cells of the immune systems found throughout the central nervous system (CNS) are known as microglia. These cells are found in the brain and spinal cord and play key roles in protecting neurons of the CNS from pathogens and other foreign substances. Malfunction in microglia has been found to be associated with many neurological diseases such as Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis (ALS). Techniques such as gene therapy to replace gene in these defective cells for proper function has shown much promise in eliminating such neurological disorders.
Unfortunately, in vitro or the use of animal models have been largely unsuccessful in fixing these microglia. In a study published in Cell Reports the researchers built upon a previous research where the team recognised that when drugs have been administered to eliminate all existing microglia, those that remained had the ability to proliferate. This then led them to discover that a trigger is required to create a microglial cavity for new microglia to grow.
Through this discovery the researchers replicated this effect by feeding normal adult mice for two weeks with a diet that included a drug inhibiting the production of a molecule required for microglial survival. Following the elimination of the microglia, bone marrow stem cell transplant was attempted for differentiation to microglia. From this, the results presented to be 93 percent of microglia were replaced in the brain, 99.5 percent in the retina, and 93 percent in the spinal cord.
The team then named the technique microglia replacement by bone marrow transplant (mrBMT), where almost all old microglia are replaced by new ones.
"We pronounce the acronym for the technique 'Mister BMT'," said Bo Peng, the corresponding author and professor from the Institute for Translational Brain Research at Fudan University. "It's a cute name, but it makes it easy to say and to remember."
Due to the lack of availability of bone marrow cells, the researchers developed a second technique using the more easily acquired peripheral blood cells (PBC) instead. This technique called “mrPB”, was able to replace 80 percent of microglia. By comparison, mrPB was less efficient in microglia replacement despite the availability of donor cells.
Further adjustments to the concept were made to cater to patients who might need microglia replacement in specific parts of the brain. First, mrBMT was used to replace resident microglia cells, then tamoxifen was administered to induce a fragment of a diphtheria toxin to kill off the replaced mrBMT cells. This was done at the same time as injecting normally functioning microglia to a specific region of the brain. These microglia are not responsive to tamoxifen. This third technique called “mrMT” was able to produce microglia almost indistinguishable from the normal kind.
"Each of the three approaches has its own merits and limits," said Bo Peng, "but each is also more appropriate for different application scenarios. The hope is that all three of them open up a new era for treating microglia-associated CNS disorders.