RESEARCH SHOWS STEM CELL POTENTIAL TO AID PARKINSON'S, OTHER DISEASES
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RESEARCH SHOWS STEM CELL POTENTIAL TO AID PARKINSON'S, OTHER DISEASES
ATLANTA, October 16, 2006 - Recent research has identified two genetic transcription factors that play central roles in embryonic stem cells into dopamine neurons found in the midbrain, a potential path to a treatment for Parkinson's. New work also has identified the molecular markers that distinguish the dopamine neurons that die and can be replaced in Parkinson's disease, and derived such neurons from embryonic stem cells.
In other reports, scientists have determined how to convert mouse embryonic stem cells to motor neurons. Recent research also shows that learning helps stem cells and neurons survive in the hippocampus.
Nesting inside a developing embryo are the primitive but versatile embryonic stem cells that are capable of maturing into any type of cell in the body. Each of these immature cells awaits its marching orders -- the biological signals that will instruct it to specialize into a brain cell, for example, that produces the chemical messenger dopamine, or a cardiac cell that will enable the heart to beat, or a pancreatic cell that will manufactures insulin.
Scientists are identifiying these biological signals so that one day embryonic stem cells (ESCs) in laboratory dishes can be coaxed to follow the developmental pathways that produce the type of brain cells that can be used therapeutically to replace cells damaged by Parkinson's disease, Lou Gehrig's disease and other neurodegenerative disorders.
"Our growing knowledge of stem cell signaling provides new ways to stimulate cell growth in the laboratory and new clinical tools based on the principles that normally control brain development and regeneration," says Ronald McKay, PhD, of the National Institute of Neurological Diseases and Stroke. He will chair a symposium on basic research with stem cells at Neuroscience 2006 in Atlanta.
Parkinson's disease, many researchers say, may be the first neurodegenerative disorder that will be experimentally treated with cells derived from ESCs in the laboratory. The laboratory-derived cells would replace the human brain cells that normally produce the chemical messenger dopamine. In Parkinson's disease, the dopamine-producing cells are damaged.
Clinical trials have already shown that surgical transplants of dopamine-producing cells can be effective. However, in these trials, these transplanted cells were derived from aborted fetal tissue, not ESCs in the laboratory. The use of fetal tissue as the source of dopamine producing cells was abandoned because of ethical and logistic issues and inconsistent results.
Recent research has identified two genetic transcription factors that play central roles in embryonic stem cells into dopamine neurons found in the midbrain.
"Clinical trials using fetal dopamine producing cells provided proof-of-principle that dopamine neurons can survive and function in the brains of patients with Parkinson's disease and, in some cases at least, may provide long-lasting clinical improvement," says Anders Björklund, PhD, of Lund University in Sweden.
Before ESCs can be safely and effectively used to replace damaged dopamine neurons of people with Parkinson's, scientists must learn much more about how to replicate in the laboratory the characteristics of the neurons that they will replace. Björklund's labs have identified two transcription factors that play central roles in inducing dopamine neurons with a correct midbrain identity.
The two factors -- encoded by genes that are named Lmx1a and Msx1-transcribe a DNA recipe for a protein so that the cell can manufacture it according to specifications.
When introduced into embryonic stem cells, these genes can activate a normal developmental program and induce robust induction of dopamine neurons in tissue culture, says Björklund.
Before people with Parkinson's disease can be treated with ESC derived dopamine producing cells, much needs to be learned, he says.
"The development of the dopamine cell replacement therapy will critically depend on the producing alternative sources of cells for transplants, as well as laboratory procedures that will allow the generation of standardized, safe, transplantable and fully functional midbrain dopamine neurons from stem cells or expandable neural progenitors," adds Björklund.
A human ESC can develop into any kind of cell in the body, including all of some 300 specific nerve cell types that populate and make up the brain. Two types of well-defined nerve cells in the midbrain produce dopamine. One, called A9, is involved in movement control and another, called A10, in emotional states.
In other research, scientists have identified the molecular markers that distinguish the dopamine neurons that die and can be replaced in Parkinson's disease, and derived such neurons from ESCs.
"Identifying these markers is crucial," says Ole Isacson, MD, PhD, of McLean Hospital and Harvard Medical School.
While there are now several ways to grow dopamine neurons from human embryonic stem cells, scientists have not yet been able to produce sufficient numbers of dopamine cells with the characteristics usually found in the brain's substantia nigra, the region where dopamine-producing neurons are lost in Parkinson's disease. Not all dopamine neurons are the same, says Isacson. Those in the substantia nigra, called A9 cells, go to motor regions of the brain, while nearby A10 cells go to the limbic system.
Isacson's laboratory has found a specific marker, called Girk2 -- G-protein-coupled inward rectifying current potassium channel type 2 -- that distinguishes A9 cells from A10 cells.
Isacson and his colleagues are continuing studies using microarrays, cell sorting, and other techniques to better define these neurons. These efforts should help researchers to grow A9 neurons from stem cells and select the best cells for future therapies.
"We must carefully select the right type of dopamine neurons for future cell therapy for Parkinson's disease," he says.
Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is another neurodegenerative disorder that scientists hope can be treated one day with cells derived from ESCs in the laboratory. Hynek Wichterle, PhD, at Columbia University, has determined how to convert mouse embryonic stem cells to motor neurons, the nerve cells that control muscles and the cells damaged in ALS.
Wichterle describes how changing concentrations of two signaling molecules specify the position of new motor neurons within the spinal cord and determine which muscles the motor neurons will innervate.
In response to decreasing concentration of retinoic acid and increasing concentration of fibroblast growth factor, motor neurons will shift downward from the cervical area, at the top of the spinal cord, to the brachial level, which includes the lower portion of the the cervical area that supplies the nerves to the arms, shoulders and chest.
"Importantly, in addition to shifting their spinal position, these motor neurons will take on the characteristics that these new cells need to function effectively at their new position in the spinal cord, such as their ability to innervate arm muscles," says Wichterle.
"In laboratory culture dishes, we can recapitulate large segments of embryonic development in order to identify the biological differences that characterize distinct groups of motor neurons," he adds.
These differences might underlie their differential susceptibility to degeneration in motor neuron diseases such as ALS. "Such biological differences might be exploited as potential targets for therapeutic intervention in the near future," says Wichterle.
New research also includes the reservoir of adult stem cells that populate an area of the human brain, the hippocampus, that is crucial to certain types of learning and memory.
These adult stem cells, which are genetically capable of maturing into any of the types of cells that make up the brain, are a scientific puzzle. Many of the thousands of stem cells that are created daily in our brains will die within weeks, but the process of learning can rescue them, says Tracey Shors, PhD, of Rutgers University.
"Nearly 10 years ago, we found that learning contributes to the survival of the new brain cells produced in the hippocampus," she says. "But, we still do not know what is it about learning that rescues these cells from death."
To answer that question, Shors trained laboratory animals on a variety of tasks that varied in difficulty and their dependence on the hippocampus."The results suggest that learning is important, and that learning more difficult types of associations are especially effective," Shors says.
"Simply put, it seems that if the animal learns, more new cells survive and go on to become neurons and if the animal does not learn, many cells die," she adds. "It is not an all or none phenomenon but rather a correlation such that the better an animal learns, the more cells that remain in the hippocampus."
