MI tracks stem cell delivery and uptake

Molecular imaging could figure prominently in the exploration and development of stem cell research's therapeutic potential by providing "eyesight" for the burgeoning field. Currently confined in large part to investigation in animal models, stem cell therapy has almost limitless potential in theory. The stem cell's ability to differentiate into a multitude of cell and tissue types offers at least a theoretical capability to repair, regenerate, or grow almost any type of tissue or organ. Whether the enthusiasm sparked by preclinical work pans out clinically remains to be seen, but molecular imaging promises to be at the center of efforts to target and monitor the progress of stem cell therapy.

"There are potentially unlimited applications for stem cells," said Dr. Jeff W.M. Bulte, an associate professor of radiology at Johns Hopkins School of Medicine. "People have shown that in many different animal models."

In an address at the International Society for Magnetic Resonance in Medicine meeting in May, German investigator Dr. Matthias Hoehn of the Max Planck Institute of Neurology reviewed the status of stem cell investigation. He said that ongo ing studies, mostly experimental, are exploring the potential of stem cells in the treatment of stroke, multiple sclerosis, spinal cord injuries, liver disease, and pancreatic islet cell transplantation.

Other neurologic investigations focus on Parkinson's and Alzheimer's disease, Bulte said.

The most advanced area of research involves the use of stem cells to treat heart conditions, including the repair of myocardium after infarction. Clinical trials have begun in Europe, and trials are planned at several centers in the U.S.

OVERCOMING OBSTACLES

All of the investigations, whether preclinical or clinical, encounter similar obstacles that molecular imaging helps overcome. Whether implanted directly at a target site or injected intravenously, stem cells need to be followed. Questions abound: Where do the cells go after introduction? When they reach the target site, how do they behave? Do they migrate to other sites, and, if so, how do they behave? Do stem cells cause unintended or harmful effects?

"It's not clear in clinical studies if stem cells that reach a certain point remain there," said Dr. Dara Kraitchman, an assistant professor of radiology at Johns Hopkins. "We need some method of visualizing the injection as well as determining where stem cells are at some later time. That's why MR labeling and MR fluoroscopic delivery of stem cells could have enormous benefit in terms of looking at stem cells after myocardial infarction."

In a lecture at the 2004 Society for Cardiovascular Magnetic Resonance meeting, Kraitchman said MR stem cell imaging has several potential applications in the evaluation of myocardial infarction and heart failure. It can assess infarct size, global function, and regional wall function.

Investigators have shown that labeled cells injected into the heart after experimental myocardial infarction express cardiac markers such as troponin T, indicating the cells have differentiated into cardiac myocytes. In the clinical setting, the success of stem cell therapy will require a method to determine the fate of injected stem cells. MR methodology has the potential to identify short-term outcomes that predict long-term prognosis, she said.

In the myocardium, MI techniques have considerable value because they supply information unavailable through other means.

Investigation of labeling materials has focused in large part on existing agents. Protamine sulfate and iron oxide compounds (ferumoxides) have been evaluated extensively. Protamine sulfate has been available for three decades as a treatment for heparin toxicity, said Dr. Ali Syed Arbab, a stem cell imaging investigator at the Henry Ford Health System in Detroit. Iron oxide agents have been used extensively for imaging small tumors and metastases in the liver.

Arbab and his colleagues have combined protamine sulfate and ferumoxides into a complex contrast agent that offers advantages over either agent alone. Ferumoxides has a negative surface charge, similar to the cells in which the contrast is to be incorporated, he said. Protamine sulfate has a positive charge and, when combined with ferumoxides, results in a contrast that is more readily incorporated into cells than either agent alone.

"With the combination, you can label cells within two hours. Without the combination, you might have to wait 48 hours or more for adequate uptake," Arbab said.

Arbab hopes the complex contrast agent will receive investigational new drug approval from the FDA by the end of the year. If the approval is granted, his group and investigators at the National Cancer Institute plan to move ahead with a clinical evaluation of molecular imaging of progenitor endothelial cells to provide more efficient presurgical mapping of glioma.

The glioma studies would be designed to map tumor angiogenesis and neovascularization and, in the process, better define the tumor border. Gliomas are difficult to differentiate from normal brain tissue, and surgeons frequently leave behind small amounts that subsequently grow into larger recurrent tumors, Arbab said. By using labeled endothelial progenitor cells, investigators can map areas of tumor expansion, which requires new blood vessels, and guide surgeons to more complete resection of gliomas.

Despite encouraging preclinical results, widespread clinical application of stem cell therapy and stem cell imaging should remain on hold until more is known about the therapy's potential and possible risks, according to Hoehn.

"We know so little about the cell biology of the stem cell," he said. "We need more animal experiments before doing work in humans."

UNANSWERED QUESTIONS

Improvement in MR's resolution and sensitivity is also necessary, Bulte said. And the fate of contrast material remains unresolved. If cells migrate from an area, the contrast can become diluted. What happens to contrast when cells proliferate is unclear. If cells die, the label remains and is eliminated by other cells that have different properties, posing a problem in discrimination between the original cells and those that ultimately clear the contrast agent.

The place of imaging modalities other than MR remains to be determined as well. PET, SPECT, and optical imaging all show potential in the imaging of stem cells, but their ideal use has yet to be defined, Bulte said.

Finally, not all investigators are convinced that stem cell imaging will have a major role in the clinical setting.

"We will learn a lot from preclinical models that relate directly to how we use stem cells in therapeutic environments," said Dr. Christopher Contag, an assistant professor of pediatrics and radiology at Stanford University. "The biggest payoff for imaging will be advancing animal models. Many of the things we learn by imaging animals will translate into the clinic without having imaging go into the clinic. We can already image engineered stem cells as they migrate through the body by just introducing thymidine kinase and asking where the cells go. How often we need to do that, and whether it is ethically and biological prudent, I think applies to a small number of studies."