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Stem Cell Transplantation Restores Motor Circuitry in HD Mice
A GABA neuron made from human stem cells in the lab of University of Wisconsin-Madison neuro-scientist Su-Chun Zhang. GABA neurons are the brain cells whose degradation causes Huntington’s disease, a condition characterized by severely degraded motor function, among other things. Zhang and his colleagues have shown that the severe motor deficits observed in a mouse model of Huntington’s can be corrected by implanting the lab made cells. (Image: Su-Chun Zhang)
A team of scientists from Shanghai China and Wisconsin have restored motor circuitry in a neurotoxin model of HD mice by transplanting human forebrain GABA medium spiny neurons generated from stem cells.
There are a number of potential disease-modifying treatments in the pipeline, including ways to silence the HD gene. Once the disease can be successfully treated, a major question for the HD community is whether it will also be possible to restore what has been lost. There has been great interest in stem cell treatments for neurodegenerative disorders but a major question has been whether they can replace lost brain cells and be able to project to and receive input from other cells. In addition, there has been concern about tumor creation or tissue overgrowth based on results in animal studies so there is a great need to be able to ensure that the cells properly differentiate into the appropriate neurons – medium spiny neurons (MSNs) in the case of Huntington’s disease.
In this new study, the researchers worked with quinolinic acid lesioned mice. While this model does not entirely reproduce all of HD pathology, it does cause extensive brain damage in the basal ganglia and severely impairs movement as does Huntington’s disease. They attempted repair by the transplantation of human embryonic stem cells which had been treated with sonic hedgehog (SHH), a signaling protein, at a specific effective dosage which led them to become DARPP32+ expressing gamma-aminobutyric (GABA) medium spiny neurons (MSNs). These are the neurons which are subject to neurodegeneration in the striatum of HD patients. DRPP32 stands for dopamine- and cyclic AMP-regulated phosphoprotein of molecular weight 32 kDA. It is mostly found in neurons which use GABA as their major neurotransmitter and it plays a central role in multiple signaling pathways.
Four months after the transplant, these forebrain GABA MSNs had repopulated the striatum. The MSNs connected to other existing cells, projected to the substantia nigra, and received inputs of the neurotransmitters glutamine and dopamine as in a normal brain. Motor function was restored as measured by the rotarod (how long the animal could stay on a revolving rod), the open field test, and a Treadscan test which shows if chorea is occurring.
The researchers also generated spinal cord GABA MSNs (which do not express DARPP32+) to see if the good results were dependent on the generation of precisely the right GABA MSNs. The spinal cord GABA MSNs did repopulate the striatum but failed to project to targets or receive input from neurotransmitters. In contrast to the results when forebrain GABA MSNs were transplanted, the motor circuitry was not restored and movement remained impaired. The study suggests that pluripotent stem cells (stem cells capable of becoming any time of cell) can be used to restore lost brain cells and function but they must be directed to become just the right type of brain cell needed.
"This is really something unexpected," says Su-Chun Zhang, a University of Wisconsin-Madison neuroscientist and the senior author of the new study. "Many in the field feel that successful cell transplants would be impossible because it would require rebuilding the circuitry. But what we've shown is that the GABA neurons can remake the circuitry and produce the right neurotransmitter."
The authors call for testing the results of this technique in HD models for a longer period of time before considering clinical trials. However, the finding that human embryonic stem cells can be treated to become forebrain GABA MSNs which can project and receive input and restore motor circuitry is very good news.
Lixiang Ma, Baoyang Hu, Yan Liu, Scott Christopher Vermilyea, Huisheng Liu, Lu Gao, Yan Sun, Xiaoqing Zhang, and Su-Chun Zhang. “Human Embryonic Stem Cell-Derived GABA Neurons Correct Locomotion Deficits in Quinolinic Acid-Lesioned Mice.” Cell Stem Cell 6 April, 2012 Volume 10, Issue 4, pp. 455-64.