Researchers reported this week that in a mouse model of Rett syndrome, they were able to improve many of the symptoms of the disorder by giving the animals a bone marrow transplant of healthy cells.

The critical cell type for those improvements, which included motor control and breathing, appeared to be microglia – immune system cells that are born in the bone marrow, but move to the brain, where they play a role in phagocytosis, or debris clearance.

Senior author Jonathan Kipnis stressed that what his team observed is "not a reversal – it's an arrest." That is, the animals were transplanted at the age where neurological symptoms begin to appear, not after such symptoms already were present to any great degree. When his team transplanted older animals, the results were much more modest.

Asked whether he believed that later transplantation would be able to reverse such symptoms with changes to the experimental procedure, Kipnis was circumspect. "I don't have the answer to that," he told BioWorld Today. Kipnis is an associate professor at the University of Virginia School of Medicine.

But, he pointed out, a sea change in the perception of Rett syndrome came after a seminal 2007 paper showed that reintroduction of a functioning MeCP2 gene into knockout mice could reverse their symptoms even once the disease was in an advanced stage.

That paper showed that in principle, it is possible to repair the damage that Rett does, even when that damage is already severe. And so, Kipnis said, "I am very hopeful" that reversal through bone marrow transplants, too, is possible.

The paper is one of several in the past few years that has expanded researchers' concept of what goes wrong in the disorder.

Genetically, Rett syndrome is a simple disorder, caused by mutations in the gene for methyl-CpG-binding protein 2, or MeCP2. MeCP2, a transcriptional regulator whose function is to methylate other genes, is expressed in most cells of the body. Rett syndrome is characterized by autism-like deficits in communication, but also by sometimes severe physical disabilities that can include breathing problems and loss of motor control.

Still, the most severe deficits are neurological. "Rett syndrome was centered around neurons, always." Kipnis said. That is, until studies showed that when only astrocytes – a type of brain support cell – expressed MeCP2 in otherwise knockout mice, many of the symptoms of the disease were improved.

In their studies, which were published in the March 18, 2012, advance online edition of Nature, Kipnis and his team showed that there is a similar improvement when MeCP2 is restored to microglia.

When the team transplanted MeCP2-deficient mice with regular bone marrow, the animals – whose growth is normally stunted – grew to normal size. The animals also lived longer and had improvements in motor function.

Perhaps the most striking improvements were to their ability to breathe. Rett patients often suffer from both hyperventilation and apnea, or brief stops in breathing. In the Rett syndrome mice, Kipnis said, those breathing abnormalities were not completely eliminated, but were strongly reduced.

To Kipnis' surprise, the specific cells that appeared to be responsible for the improvements were microglia – his money had been on T cells, which his team had previously implicated in learning, as the immune cells that would have the most effect on Rett syndrome. (See BioWorld Today, May 10, 2010.)

"I thought it would be other cells," he cheerfully acknowledged. "But I was wrong."

Instead, for bone marrow transplants to have an effect, it turned out to be critical that MeCP2-expressing microglia were able to return to the brain and fulfill one of their major functions, namely phagocytosis.

The paper joins several others that have shown it is possible to affect the symptoms of Rett syndrome, for better or for worse, by adding or removing MeCP2 in one specific cell type – glial cells, inhibitory interneurons and, now, microglia. (See BioWorld Today, Nov. 15, 2010.)

Kipnis said that, together, the papers suggested that "there is a very complex interaction between the three cell types."

The ultimate cause of symptoms is dysfunctional neurons. But those neurons work within an environment of other cells that can themselves be functional or dysfunctional. And so, "what microglia are probably doing is providing a healthier environment."