“The most exciting part of this research is that it offers the promise of direct disease modeling by the creation, in a Petri dish, of mature human neurons that behave a lot like the neurons that grow naturally in the human brain,” said Chen, a professor of biology and the Verne M. Willaman Chair in Life Sciences at Penn State. Chen said that the method could lead to customized treatments for individual patients based on their own genetic and cellular information.
“Obviously, we don’t want to remove someone’s brain cells to experiment on them, so recreating the patient’s brain cells in a Petri dish is the next best thing for research purposes and drug screening,” he said. The research will be published in the journal Stem Cell Research. More information and a photo are online at science.psu.edu/news-and-events/2013-news/Chen6-2013.
“Previous researchers could obtain brain cells only from deceased patients who had suffered from diseases such as Alzheimer’s, schizophrenia and autism,” Chen said. “Now, researchers can take skin cells from living patients — a safe and minimally invasive procedure — and convert them into brain cells that mimic the activity of the patient’s own brain cells.”
Chen added that, by using this method, researchers also can figure out how a particular drug will affect a particular patient’s own brain cells, without needing the patient to try the drug — eliminating the risk of serious side effects. “The patient can be his or her own guinea pig for the design of his or her own treatment, without having to be experimented on directly,” he said.
Chen explained that, in earlier work, scientists had found a way to reprogram skin cells from patients to become unspecialized cells called “pluripotent stem cells,” (iPSCs), which Chen said are kind of like a blank slate. “During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell or a blood cell. So, after generating these iPSC cells from skin cells, researchers then can culture them to become brain cells, or neurons, which can be studied safely in a Petri dish.”
Now, in their new research, Chen and his team have found a way to differentiate iPSCs into mature human neurons much more effectively, generating cells that behave similarly to neurons in the brain. In their natural environment, neurons in the brain are always found near star-shaped cells called astrocytes, which help the neurons to function properly. “Because neurons are adjacent to astrocytes in the brain, we predicted that this direct physical contact might be an integral part of neuronal growth and health,” Chen explained. And what his Petri dish experiments showed was that neural stem cells cultured on astrocytes did differentiate into mature neurons much more effectively than those cultured without contacting any astrocytes “It was almost as if the astrocytes were cheering the stem cells on, telling them what to do, and helping them fulfill their destiny to become neurons,” Chen said.
The scientists also found that the cells grown on astrocytes sent many more signals from one nerve cell to the others. In another experiment, after growing the neural stem cells next to astrocytes for just one week, the researchers showed that the newly differentiated neurons started to fire action potentials — the rapid electrical signal that occurs in all neurons in the brain. In a final test, the scientists added human neural stem cells to a mixture with mouse neurons and found that the neurons were contacting their neighbors by releases a chemical called a neurotransmitter to influence its neighbor’s activity. “We found that, after just one week, there was a lot of this ‘cross-talk’ between the mouse neurons and the human neurons,” Chen said.
In addition to Chen, other researchers who contributed to this study include Xin Tang, Li Zhou and Alecia M. Wagner from Penn State; Maria C.N. Marchetto and Fred H. Gage from the Salk Institute; and Alysson R. Muotri from the University of California at San Diego.
The research was funded by the Penn State Stem Cell Fund, the National Institutes of Health, the JPB Foundation, the Mathers Foundation, the McDonnell Foundation and the California Institute for Regenerative Medicine.