Inflammation is generally considered to be harmful to neurons. But a mice study finds that cell fusions during inflammation protect neurons from harm, scientists at the Stanford University Medical Center have revealed.
The study suggests that chronic inflammation triggers bone marrow-derived blood cells to travel to the brain, and fuse with a certain type of neuron up to 100 times more frequently than earlier thought, say the researchers.
AdvertisementOnce the fusion occurs, add the researchers, the blood-cell nuclei starts expressing previously silent neuron-specific genes.
According to them, the study goes to suggest that the fused cells, heterokaryons, may play a role in protecting neurons against damage.
The researchers also say that the study's results may open new doors to cell-mediated gene therapy.
"This finding was totally unprecedented and unexpected. We're getting hints that this might be biologically important, but we still have a lot to learn," Nature magazine quoted senior author Dr. Helen Blau, the Donald E. and Delia B. Baxter Professor and director of the Baxter Laboratory in Genetic Pharmacology, as saying.
Known as blood stem cells or hematopoietic stem cells, the bone marrow-derived cells can give rise to all the blood and immune cells in the body.
Previous studies have shown the progeny of such cells fuse with a variety of other cell types in the body, but this fusion has been thought to have little biological significance to date because it occurs very infrequently.
Purkinje neurons are large cells in a portion of the brain known as the cerebellum, which is involved in balance and motor control. They form junctions between many other neurons, and they do not regenerate.
They are the only cell in the brain shown by Blau and others to fuse with these bone marrow-derived cells in mice and humans.
In their current study, the researchers used a technique called parabiosis to introduce blood cells expressing green fluorescent protein into an unmodified animal.
During the procedure, two mice are surgically joined in such a way that they share a circulatory system. One mouse had been engineered to express the green protein in all its cells, while one not.
The researchers found evidence of fusion between blood cells and Purkinje neurons in this radiation-free system 20 to 26 weeks after surgery. They revealed that green heterokaryons were identifiable for up to 20 weeks after the mice were separated, when most of the blood cells in the unmodified mouse had been regenerated as non-coloured cells.
The researchers observed that some of the mice had almost 100 times more fused cells in their cerebellums that most others.
Upon investigating the difference closely, they found that the animals with higher-than-expected numbers of fused cells also had an inflammatory skin condition common to aging laboratory mice called idiopathic ulcerative dermatitis, which affects the entire immune system of the animal and causes a systemwide immune response.
The research team confirmed that the remarkable increase in the numbers of fused cells was related to inflammation by using the traditional radiation/bone marrow transplant approach in mice with dermatitis.
They finally counted the fused cells that formed in a mouse model of multiple sclerosis, an autoimmune disease characterized by inflammation and damage of the central nervous system, and found that heterokaryons in some of the mice numbered in the thousands.
Even more intriguing than the inflammation-induced increase in numbers was a cross-species experiment that showed nuclei from rat blood stem cells that had fused to Purkinje cells in mice stop expressing blood cell proteins and begin to express rat neuron-specific gene products.
This switch exemplifies a type of genetic reprogramming that has been a source of ongoing debate and great interest in the world of stem cell research. Such reprogramming is critical to the regeneration of functional tissues by stem cells, say the researchers.
"What we're seeing is that this phenomenon is happening in real life. We don't know yet if this function is beneficial, but we now know that there are sites where it happens at fairly high frequencies under certain conditions, and that these nuclei can even be reprogrammed," said Blau, who next plans to study whether such fusions can rescue damaged or dying Purkinje neurons.