Immature neurons transplanted into the brains of obesity-prone mice can prevent the animals from becoming so fat, according to a new study. The researchers caution that their experiment was never intended as a step toward treating obesity in humans, but they say it provides an important proof of principle that transplanted fetal cells can integrate themselves into an abnormal neural circuit and help restore its function. Other researchers say the work highlights both the promise and the challenges of developing cell therapies for complex brain disorders.
The road to fetal or stem cell therapies for the nervous system has been rocky. Despite early promise, recent trials of fetal cell transplants for Parkinson's disease have yielded disappointing results, for example, and last week the California biotechnology company Geron pulled the plug on a closely watched trial of a stem cell therapy for spinal injury. It also announced that, for financial reasons, it would abandon further stem cell work.
Yet basic neuroscience research has been more encouraging. In the past decade, scientists overturned century-old dogma by showing that some parts of the human brain produce new neurons throughout life. There is evidence that these new neurons get wired into existing neural circuits and may help maintain or enhance brain function, suggesting that transplanted cells may be able to do the same.
In the new study, reported online today in Science, Harvard University neuroscientist Jeffrey Macklis and colleagues investigated whether fetal neurons transplanted into a part of the mouse brain that does not normally produce new neurons of its own could repair an abnormal neural circuit. The recipients of the transplant treatment were genetically altered mice lacking the receptor for leptin, a hormone that regulates metabolism and body weight. In normal mice, leptin acts on neurons in a part of the brain called the hypothalamus, which regulates metabolism and other essential functions. But in the mutant mice, these neurons can't respond to leptin, and the mice become obese and diabetic.
To see whether they could correct this defect, the researchers transplanted immature neurons taken from the hypothalami of fetal mice that had the normal leptin receptor gene into the same brain region of the obesity-prone mice. Mice that got transplanted cells a few days after birth grew up to be significantly chubbier than normal but not morbidly obese, Macklis and colleagues found. The rodents with transplanted cells weighed about 40 to 45 grams on average, compared with 25 grams for normal mice and 55 to 60 grams for mutant mice that received a sham operation but no neurons. Also, they were not diabetic.
The team used several methods to examine how the transplanted neurons fared. The transplanted neurons had a gene for a protein that glows green in certain light, and using this and other markers, the researchers saw under the microscope that the cells had differentiated into several different types of neurons normally found in the hypothalamus and had formed synaptic connections with other neurons. Using electrodes to record the electrical activity of hypothalamic neurons, the researchers confirmed that the transplanted cells responded to leptin as expected and could communicate with the recipient mouse's own neurons. "These newly incorporated neurons were in a sense acting as antennas for leptin and sending those signals into the brain," Macklis says.
Macklis says the lessons learned from these experiments could help researchers trying to develop cell therapies for conditions such as amyotrophic lateral sclerosis, Parkinson's disease, and spinal injury. Using exactly the right cells, either by carefully selecting cells to transplant and precisely guiding their development or by incorporating immature neurons already present in the adult brain, will be crucial, he says.
In the new study, his group transplanted immature cells that were just at the stage of differentiating into several types of hypothalamic neurons. Additional experiments showed that fetal cells taken slightly later in development or from a different part of the brain did not prevent or reduce obesity when transplanted into the mutant mice. "These experiments say that if you get the neurons just right, it's possible for the adult brain to accept them, to wire them in, and have them fully functional."
"The work is obviously very carefully done," says Evan Snyder, a stem cell researcher at the Sanford-Burnham Medical Research Institute in San Diego, California. The findings, he says, add to a growing realization that cell therapies will have to be tailored to the specific neural circuit that's affected. In the optimistic early days of the field, Snyder says, scientists hoped that simply transplanting stem cells or neural progenitors into a brain would repair neural circuits because cues in the cellular environment would tell the new cells what to do. That's turning out not to be the case. "Reconstructing a circuit is going to require knitting together a number of specialized cells and not relying on the environment to do it," he says. "I'm still optimistic, but there's going to be a lot of intellectual heavy lifting."