Stemming GI Disorders

To illustrate the gastrointestinal problems she's trying to fix using stem cells, Maria-Adelaide Micci rolls up a piece of paper, then pinches it in the middle. "Look at the gut as a tube," the UTMB assistant professor says. "If you have a tube and you squeeze, it's going to be pushing whatever is downstream down, and then as you relax whatever is upstream keeps going down." By alternating contraction and relaxation, the gastrointestinal system smoothly moves material from the top of the stomach through the bottom of the colon. "But if the neurons that tell the muscle to relax don't work," Micci says, "you have a problem, because you cannot push anything down if the muscle is not relaxing."

When that happens, you get disorders with names like achalasia, pyloric stenosis, and Hirschsprung's disease-painful, debilitating conditions now only partly correctable by surgery. "In achalasia, for example, where the lower esophageal sphincter-the ringlike muscle at the base of the esophagus-fails to relax, patients have trouble swallowing," says UTMB Professor P. Jay Pasricha, Micci's collaborator and the principal investigator on the National Institutes of Health grant which funds her stem-cell work. "We try to destroy the sphincter with surgery, to cut the muscle, but the sphincter is not the problem. The problem is the nerves, and the only way to cure achalasia is to replace the nerves."

Micci and Pasricha want to implant stem cells that will mature into neurons to replace those not doing their jobs. Experiments in cell cultures and with rats and mice over the last three years suggest that they're on the right track.

Working with neural stem cells taken from the brains of embryonic rats-cells already in the process of becoming specialized neurons-Micci found that in cell culture they produce nitric oxide, the chemical that signals muscles to relax. They retained this ability after they differentiated into fully developed neurons, and they also produced the proper receptor molecules to respond to GDNF, a cell growth factor abundant in the enteric nervous system, the autonomous network of nerves that controls the gastrointestinal system.

Then, when stem cells were injected into adult mice's pyloric sphincters-the circular muscles that control the exit from the stomach (and that refuse to relax in pyloric stenosis)-they survived up to eight weeks, developed into neurons and glia (cells that support neurons), and produced neuronal nitric oxide synthase, the enzyme used to make nitric oxide.

"Right now, we've proven we can inject the cells into mice and these have the potential to become neurons and make nitric oxide," Micci says. "The main goal, long-term, is to make this work in patients."

In mice, Micci plans to monitor cell survival for as long as one year after implantation, comparing stem cell survival rates in animals whose immune systems are suppressed with survival rates of non-immunosuppressed animals to see whether immune rejection influences transplant success. Working in lab dishes, she hopes to find ways to improve stem cells' survival and promote their development into neurons. Finally, she aims to explore whether the cells improve the digestion of "knockout mice" genetically engineered with an enteric nervous system incapable of making nitric oxide.

"These are very malleable, almost magical cells-they have a tremendous ability to adapt and respond to cues in the environment," Pasricha says. "It's kind of uncharted territory, and we're going step by step."
-Jim Kelly