The study, “Human Stem Cell-Derived Neurons Repair Circuits and Restore Neural Function,” was published in the journal Cell Stem Cell.
Stem cells are able to continuously divide and transform into other types of cells. Because of this ability, stem cells have gained interest as treatments in a number of fields, including regenerative medicine for neurological conditions such as Parkinson’s.
Stem cell therapy uses stem cells to cultivate new and healthy cells, tissues or organs, that are then transplanted back into patients to restore physiological functions lost to damaged or dead cells.
In the context of neurodegenerative diseases, the basic concept is that stem cells could be used to “replace” brain nerve cells (neurons) that become damaged during the course of the disease.
Researchers at the University of Wisconsin–Madison now investigated a stem cell treatment in a mouse model of Parkinson’s disease and found that neurons derived from stem cells can integrate into the correct regions of the brain, connect with native neurons, and restore motor functions.
“Neurological injuries usually affect specific brain regions or specific cell types, disrupting circuits. In order to treat those diseases, we have to restore these circuits,” Su-Chun Zhang, MD, PhD, a professor of neuroscience and neurology at UW–Madison’s Waisman Center, said in a press release.
In an attempt to repair damaged neural circuits, the team began by developing two types of neurons from human embryonic stem cells (hESCs): dopaminergic neurons — those that are responsible for producing dopamine, a neurotransmitter that plays a key role in regulating motor function — or glutamate-producing neurons. Glutamate is another type of neurotransmitter, or chemical messenger, that plays an important role in learning and memory.
These hESC-derived dopaminergic neurons were transplanted into Parkinson’s mice to two midbrain areas, the striatum and the substantia nigra, which are involved in motor control and severely affected in Parkinson’s.
Six months after transplantation, grafts from both types of neurons were present in all animals, showing that the transplanted neurons were able to differentiate to respective neuronal types and also project to different brain regions.
Upon examination of mice brain sections, months after being transplanted, researchers found that transplanted neurons were able to establish neural connections (synapses) with neurons from the hosts’ brains, suggesting extensive graft integration into the host circuitry.
To understand the specific patterns of distribution of transplanted dopamine-producing neurons, researchers genetically labeled those cells, which allowed them to follow them visually as they grafted and matured in the hosts’ brains.
Six months later the team observed that transplanted neurons exhibited physiological and functional characteristics from native neurons. Also, grafted neurons received inputs from different brain regions in a pattern similar to native neurons in a location-dependent manner (i.e., depending on the site where they were transplanted).
The team then examined the functional effect of transplanted cells, using different motor tests, before and every four weeks after transplant.
Mice that received dopamine-producing neurons in their striatum or substantia nigra began to recover motor function as soon as three months after being transplanted. In contrast, animals that were transplanted with neurons that produced glutamate did not recover from motor deficits.
These results show that the identity of the grafted neurons, rather than the site they home to, determine their own signaling characteristics and functionality, highlighting the need for the correct cell types for cell therapy.
Finally, to determine whether the observed motor recovery depended on the reconstructed neural circuit, scientists used something called a bi-directional switch; transplanted neurons were genetically modified so they could be switched on or off when exposed to certain chemicals.
When the transplanted dopaminergic neurons were “shut down,” motor improvements no longer were observed, suggesting that these cells were responsible for the restoring the damaged connection in animals’ brains.
Based on these results, researchers believe cell-based therapy to treat neurological conditions is a realistic goal. However, they recognize that more research is necessary to translate findings from mice to people.
To that end, Zhang’s group is currently testing similar treatments in primates, a step toward human trials.
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