Researchers discovered that chronic inflammation triggers hematopoietic stem cells to travel to the brain and fuse with Purkinje neurons up to 100 times more frequently than previously believed. After the fusion, the blood-cell nuclei (heterokaryons) begin to express previously silent, neuron-specific genes, which may possibly play a role in protecting neurons against damage.
The researchers used lethal doses of radiation to abolish a mouse's hematopoietic system to transplant a single hematopoietic stem cell and prove that the fusion cells in the brain were derived from blood. To see if this fusion would occur even under less physiologically traumatic conditions, they used a technique called parabiosis, which surgically joins two mice in such a way that they share a circulatory system, to introduce blood cells into an unmodified animal.
The researchers found evidence of fusion between blood cells and Purkinje neurons in this radiation-free system 20 to 26 weeks after surgery. As in previous experiments, most mice had very low numbers of fused cells in their cerebellums, but a few had up to 100 times more. The scientists found that those animals with higher-than-expected numbers of fused cells also had an inflammatory skin condition common to aging laboratory mice called idiopathic ulcerative dermatitis.
The researchers confirmed that the increased number of fused cells was related to inflammation by using the traditional radiation/bone-marrow transplant approach in mice with dermatitis and in a mouse model of multiple sclerosis.
Finally in a cross-species experiment the investigators showed that nuclei from rat blood stem cells that had fused to Purkinje cells in mice stopped expressing blood cell proteins and began 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, according to the investigators. Such reprogramming is critical to the regeneration of functional tissues by stem cells.
The research was a collaborative effort between Stanford University School of Medicine and the University of British Columbia. The study was published on April 20 in Nature Cell Biology.