Stem cells can repair Parkinson's-damaged circuits in mouse brains
The mature brain is notoriously poor at repairing itself after damage caused by trauma, stroke or degenerative diseases such as Parkinson's disease. The unlimited adaptability of stem cells offers hope for improved neural repair. But the complexities of precise brain tuning have hampered the development of clinical treatments.
In a new study that addresses these obstacles, researchers at the University of Wisconsin-Madison have demonstrated a proof-of-concept stem cell therapy in a mouse model of Parkinson's disease. They found that neurons from stem cells could integrate well into the right areas of the brain, connect with local neurons, and restore motor function.
The key is identity. By carefully tracking the fate of transplanted stem cells, the scientists found that the identity of the cells - in the case of Parkinson's disease, dopamine-producing cells - determines their connectivity and function.
Coupled with a growing number of ways to generate dozens of unique neurons from stem cells, the scientists say the work suggests that neural stem cell therapy is a realistic goal. However, more research is needed to translate the findings from mice to humans.
The team, led by UW-Madison neuroscientist Su-Chun Zhang, published its findings Sept. 22 in the journal Cell Stem Cell. The study was led by postdoctoral researchers in Zhang's lab, Yuejun Chen, Man Xiong and Yezheng Tao, who now hold faculty positions in China and Singapore.
"Our brains are wired by very specialized nerve cells in specific locations in such a precise way that we can engage in all kinds of complex behaviors. It all depends on circuits wired by specific cell types," said Zhang, a professor of neuroscience and neurology at UW-Madison's Waisman Center." Nerve damage usually affects specific brain regions or specific cell types, disrupting the circuitry. In order to treat these diseases, we must restore these circuits."
To repair these circuits in a mouse model of Parkinson's disease, the researchers first coaxed human embryonic stem cells to differentiate into dopamine-producing neurons, which die in Parkinson's disease. They transplanted these new neurons into the mice's midbrain, the region of the brain most affected by Parkinson's degeneration.
After a few months, after the new neurons had time to integrate into the brain, the mice's motor skills improved. On closer inspection, Zhang's team was able to see that the transplanted neurons were connected long distances to motor control areas of the brain. The nerve cells also made connections to regulatory areas of the brain that feed to the new neurons, preventing them from being overstimulated.
Both sets of connections - input and output from the transplanted neurons - are similar to the circuits established by the local neurons. This is true only for the dopamine-producing cells. In similar experiments, cells producing the neurotransmitter glutamate (not involved in Parkinson's disease) did not repair motor circuits, revealing the importance of neuronal identity in repairing damage.
To conclusively confirm that the transplanted neurons had repaired circuits damaged by Parkinson's disease, the researchers inserted genetic switches into the stem cells. These switches turn up or down the activity of the cells when they are exposed to specially designed drugs in the diet or by injection.
When the stem cells were turned off, the mice's improvement in movement disappeared, suggesting that the stem cells are crucial for restoring the brain damaged by Parkinson's disease. The study also suggests that this gene switch technique could be used to fine-tune the activity of the transplanted cells to optimize treatment.
Zhang's group and other researchers have been developing ways to convert stem cells into many different types of neurons in the brain for years. Each neurological disease or injury requires its own specialized nerve cells to treat, but the treatment options may be broadly similar." We use Parkinson's disease as a model, but the principle is the same for many different neurological disorders," Chang said.
The work has personal significance for Chang. As a physician and scientist, he often receives letters from families who are desperate for help in treating neurological disorders or traumatic brain injuries. Six years ago, Mr. Zhang suffered a broken neck in a bicycle accident. When he woke up in the hospital, partially paralyzed, his first thought was how stem cells - which he had been studying for years - could help him recover.
Now, after years of physiotherapy, Mr. Zhang has largely recovered. Mr. Zhang still believes that the right stem cell treatment can help people like him and his family in the future," he says.
To that end, Zhang's team is currently testing a similar treatment on primates, a step toward human trials.
"There's hope, but we need to take it one step at a time," he said.
