MRI Used to Track Neuronal Stem Cells

Biologists have developed a magnetic resonance imaging (MRI)-based technique that allows researchers to monitor neural stem cells noninvasively in vivo.

The recently patented technology could be used to further the study of neural stem cells and inform the development of new treatments for brain injury caused by trauma, stroke, Parkinson’s disease, and other neurologic disorders. The study, conducted by Carnegie Mellon University (Pittsburg, PA, USA), associate professor of biological sciences Dr. Eric Ahrens and biological Sciences postdoctoral student Dr. Bistra Iordanova, were published online October 2011 in the journal NeuroImage.

Scientists have long believed that once a brain cell dies, it is lost forever. Neuroscientists now know that this is purely myth, having proved that the brain is constantly producing new neurons. These neural stem cells are born deep in an area of the brain called the subventricular zone. As time goes on, the cells, also called neuroblasts, make their way to other regions of the brain where they mature into functioning neurons. The brain’s ability to regenerate its cells is of great significance to scientists.

“If we could better understand the molecular migratory signals that guide neuroblasts, we could try to redirect these cells to areas of the brain harmed by stroke or traumatic brain injury. With this information, scientists might be able to one day repair the brain,” said Dr. Ahrens, who also is a member of the Pittsburgh NMR Center for Biomedical Research.

Studying cells in a living brain is problematic. Common forms of in vivo cell imaging like fluorescence and bioluminescence rely on light to generate images, making them unsuitable for viewing neuroblasts buried deep beneath the skull and layers of opaque tissue. Until now, scientists had only been able to examine neuronal stem cells by looking at slices of the brain under a microscope. Dr. Ahrens was able to overcome this hurdle using MRI technology.

Instead of light, MRI uses magnets to create high-resolution images. A typical MRI scan uses a magnetic field and radio frequency pulses to cause the hydrogen protons found in the body’s water molecules to give off signals. Those signals are converted into a high-resolution image.

At the basis of this core is a technology Dr. Ahrens developed. As reported in a 2005 issue of the journal Nature Medicine, Dr. Ahrens devised a method that causes cells to produce their own contrast agent allowing them to be imaged with MRI. Using a viral vector, Dr. Ahrens integrated the gene that produces the naturally occurring metalloprotein ferritin into living cells. Ferritin, which is present in all biologic cells, harvests and stores naturally occurring iron. When the cells tagged with ferritin began to produce increased amounts of the protein, they draw in additional iron, turning themselves into nanomagnets. This disrupts the magnetic field surrounding the tagged cells, altering the signal given off by adjacent water molecules. This change appears as dark spots on the MRI image indicating the cells’ presence. Since then, Dr. Ahrens’ team has improved on the process, developing an engineered form of ferritin that is a more effective MRI reporter than naturally occurring ferritin.

In the current study, Drs. Iordanova and Ahrens used the same technique as in the first study, this time tagging neuroblasts with the engineered ferritin. They incorporated the DNA sequence for the modified metalloprotein into an adenovirus vector, which they then injected into the subventricular zone of a rat brain. The adenovirus infected the neural stem cells giving the cells the genetic instructions to begin producing the ferritin reporter. Dr. Iordanova then imaged the brain with MRI and found that she was able to track--in real time--the neuroblasts as they moved toward the olfactory bulb and ultimately formed new inhibitory neurons. These results mirrored what had been observed in histology studies.

Recently, Carnegie Mellon received a patent for the reporter. Dr. Ahrens hopes to continue to develop the technology in order to allow researchers to better understand neuronal stem cells and how neurons regenerate. Dr. Ahrens also plans to use the reporters to improve clinical trials of cell-based therapies. By integrating the reporter into the cells before implantation, researchers would be able to find the solution to a host of vital questions.

“Where do these cells go, days, weeks, and months later? How do we know that they’ve grafted to the right cells? Or have they grafted in the wrong place? Or died?” Dr. Ahrens asked. “The reporter can show us the answers.”

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