No other branch of science is quite so laden with expectation. But while corralling stem cells for viable therapies, researchers have found themselves asking an entirely separate question: How do we track them?
Stem cells. Call them the great translucent hope. Between clinical trials, legal challenges, and endless media reports, perhaps no other branch of science is quite so laden with expectation. For the general public, stem cells are filtered largely through the lens of hyperbole, with stem cell therapies touted as a sort of scientific second coming. For the researchers who study them, expectations are more tempered, as are the timelines for possible medical advances. Yet there's no denying the excitement; these cells represent a drug development platform, a window into the pathogenesis of disease, and of course, a potential source of transplantable therapies.
In the pursuit of implantable stem cells, though, one question often goes unanswered: Once researchers get stem cells into a body, how will they track them?
It's a question that goes to the heart of stem cell–based therapeutics. Stem cells per se are not much use therapeutically; it's what they change into— cardiomyocytes and islets and neurons, for example—that counts. Or, as James Mansfield, director of tissue analysis applications at Caliper Life Sciences, puts it, “When [stem cells] grow up, what do they become?”
Caliper is one of the companies developing technologies to address such questions. The firm (which in December acquired rival company Cambridge Research & Instrumentation) sells both fluorescence- and bioluminescence-based whole-body imagers for small animals. These imagers— basically ultrasensitive cameras in very dark boxes—enable researchers to peer past skin, tissue, and bone to visualize the stem cells within. But there are other imaging modalities too, including the acronym-rich toolset of the healthcare industry: CT, MR I, PET, and SPECT. At the moment, none of these approaches is perfect; the general consensus seems to support a multimodal approach integrating multiple orthogonal methods. New techniques are in development. In the meantime, stem cell scientists are making do with a rich and ever-growing in vivo imaging toolset.
For those researchers interested in what stem cells are doing in the body, in vivo imaging offers several obvious advantages over slide- and plate-based methods. Cells behave differently—and less physiologically—in culture than in live organisms, for one thing. In vivo experiments are also cleaner, according to Stanford University cardiologist Joseph Wu: researchers can image a single test subject repeatedly over time, instead of sacrificing several lab animals at each of several time points and then trying to make sense of the resulting, aggregated data. “There's a lot of variation from animal to animal,” Wu says.
That said, in vivo imaging isn't easy, and can be bedeviled by issues like signal penetration, scatter, resolution, and sensitivity. Stem cells add additional complexities, says Mansfield, in that they are relatively rare. “Stem cells are a small population,” he says. “Even if you inject a million cells, it's not that many when spread throughout the animal.” Couple that with the fact that the tissues researchers care about often are deeply buried, and it becomes even more difficult to track them down.
Heike Daldrup-Link, associate professor of radiology at the Stanford University School of Medicine and member of the Molecular Imaging Program at Stanford (MIPS), concentrates her research on techniques for in vivo imaging of stem cells and cancer cells. But not just any imaging modality will do. As an M.D.-Ph.D. who splits her time between the lab and the clinic, Daldrup-Link chooses methods with “very high translational potential.”
Her imaging modality of choice is magnetic resonance imaging (MRI). “Traditional MRI manipulates hydrogen nuclei in fluid under a static magnetic field to obtain regional contrasts based on differences in proton density, flow, or biochemical structure,” explains one 2007 review of cardiac stem cell tracking. To be tracked in infarcted myocardium, stem cells need to be enriched with a contrast agent that produces a sufficient positive or negative signal to distinguish them from the background (1).