Brain Cells Recreated From Skin Cells To Study Schizophrenia Safely

Main Category: Schizophrenia
Also Included In: Autism;  Bipolar;  Stem Cell Research
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A team of scientists at Penn State University, the Salk Institute for Biological Studies, and other institutions have developed a method for recreating a schizophrenic patient's own brain cells, which then can be studied safely and effectively in a Petri dish. The method brings researchers a step closer to understanding the biological underpinnings of schizophrenia. The method also is expected to be used to study other mysterious diseases such as autism and bipolar disorder, and the researchers hope that it will open the door to personalized medicine - customized treatments for individual sufferers of a disease based on genetic and cellular information. The study will be published in a future edition of the journal Nature and will be posted on the journal's advance online website on 13 April 2011.

Gong Chen, an associate professor of biology at Penn State and one of the study's authors, explained that the team first took samples of skin cells from schizophrenic patients. Then, using molecular-biology techniques, they reprogrammed these original skin cells to become unspecialized or undifferentiated stem cells called induced pluripotent stem cells (iPSCs). "A pluripotent stem cell is a kind of blank slate," Chen explained. "During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell."

After generating iPSCs from skin cells, the authors cultured them to become brain cells, or neurons. They then compared the neurons derived from schizophrenic patients to the neurons created from the iPSCs of healthy individuals. They found that the neurons generated from schizophrenic patients were, in fact, distinct: compared with healthy neurons, they made fewer connections with each other. Kristen Brennand, a Salk researcher and one of the study's authors, then administered a number of frequently prescribed antipsychotic medications to test the drugs' ability to improve how neurons communicate with neighboring cells. "Now, for the very first time, we have a model system that allows us to study how antipsychotic drugs work in live, genetically identical neurons from patients with known clinical outcomes, and we can start correlating pharmacological effects with symptoms," Brennand said.

Chen, who contributed to the study by using electrophysiology techniques to test the function of the iPSC-derived neurons, described the new method as "patient specific," offering a step toward personalized medicine for sufferers of schizophrenia and potentially other diseases. "What's so exciting about this approach is that we can examine patient-derived neurons that are perhaps equivalent to a particular patient's own neural cells," Chen said. "Obviously, we don't want to remove someone's brain cells to experiment on, so recreating the patient's brain cells in a Petri dish is the next best thing for research purposes. Using this method, we can figure out how a particular drug will affect that particular patient's brain cells, without needing the patient to try the drug, and potentially, to suffer the 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."

Lead author Fred Gage, a professor at Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases, explained that schizophrenia exemplifies many of the research challenges posed by complex psychiatric disorders. "This model not only affords us the opportunity to look at live neurons from schizophrenia patients and healthy individuals to understand more about the disease mechanism, but also it allows us to screen for drugs that may be effective in reversing it," Gage said.

Schizophrenia, which is defined by a combination of paranoid delusions, auditory hallucinations, and diminished cognitive function, afflicts one percent of the population worldwide, corresponding to nearly three million people in the United States alone. Genetic evidence indicates that many different combinations of genetic lesions - some of them affecting the susceptibility to environmental influences - may lead to a variety of signs and symptoms collectively labeled schizophrenia.

"Nobody knows how much the environment contributes to the disease," said Brennand. "By growing neurons in a dish, we can take the environment out of the equation and start focusing on the underlying biological problems." In another part of the study, Brennand used a modified rabies virus, developed by Salk professors Edward Callaway and John Young, to highlight the connections between neurons. The viral tracer made it apparent that the schizophrenic neurons connected less frequently with each other and had fewer projections growing out from their cell bodies. In addition, gene-expression profiles identified almost 600 genes whose activity was misregulated in these neurons; 25 percent of those genes had been implicated in schizophrenia before.

Gage added that, for many years, mental illness has been thought of as a strictly social or environmental disease. "Many people believed that if affected individuals just worked through their problems, they could overcome them," he said. "But we are showing real biological dysfunctions in neurons that are independent of the environment."

Notes:

In addition to Gage, Brennand, and Chen, other researchers who contributed to the study include Anthony Simone, Jessica Jou, Chelsea Gelboin-Burkhart, Ngoc Tran, Sarah Sangar, Yan Li, Yanglin Mu and Diana Yu in the Gage Laboratory; Shane McCarthy at the Cold Spring Harbor Laboratory in New York; and Jonathan Sebat at the University of California at San Diego.

The work was funded, in part, by the California Institute for Regenerative Medicine, the Lookout Foundation, the Mathers Foundation, and the Helmsley Foundation.

Source:
Barbara Kennedy
Penn State

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Dopamine Controls Formation Of New Brain Cells

A study of the salamander brain has led researchers at Karolinska Institutet in Sweden to discover a hitherto unknown function of the neurotransmitter dopamine. In an article published in the prestigious scientific journal Cell Stem Cell they show how in acting as a kind of switch for stem cells, dopamine controls the formation of new neurons in the adult brain. Their findings may one day contribute to new treatments for neurodegenerative diseases, such as Parkinson's.

The study was conducted using salamanders which unlike mammals recover fully from a Parkinson's-like condition within a four week period. Parkinson's disease is a neurodegenerative disease characterised by the death of dopamine-producing cells in the mid-brain. As the salamander re-builds all lost dopamine-producing neurons, the researchers examined how the salamander brain detects the absence of these cells. This question is a fundamental one since it has not been known what causes the new formation of nerve cells and why the process ceases when the correct number have been made.

What they found out was that the salamander's stem cells are automatically activated when the dopamine concentration drops as a result of the death of dopamine-producing neurons, meaning that the neurotransmitter acts as a constant handbrake on stem cell activity.

"The medicine often given to Parkinson's patients is L-dopa, which is converted into dopamine in the brain," says Dr Andras Simon, who led the study at the Department of Cell and Molecular Biology. "When the salamanders were treated with L-dopa, the production of new dopamine-producing neurons was almost completely inhibited and the animals were unable to recover. However, the converse also applies. If dopamine signalling is blocked, new neurons are born unnecessarily."

As in mammals, the formation of neurons in the salamander mid-brain is virtually non-existent under normal circumstances. Therefore by studying the salamander, scientists can understand how the production of new nerve cells can be resumed once it has stopped, and how it can be stopped when no more neurons are needed. It is precisely in this regulation that dopamine seems to play a vital part. Many observations also suggest that similar mechanisms are active in other animal species too. Further comparative studies can shed light on how neurotransmitters control stem cells in the brain, knowledge that is of potential use in the development of therapies for neurodegenerative diseases.

"One way of trying to repair the brain in the future is to stimulate the stem cells that exist there," says Dr Simon. "This is one of the perspectives from which our study is interesting and further work ought to be done on whether L-dopa, which is currently used in the treatment of Parkinson's, could prevent such a process in other species, including humans. Another perspective is how medicines that block dopamine signalling and that are used for other diseases, such as psychoses, affect stem cell dynamics in the brain."

The salamander is a tailed member of the frog family most known for its ability to regenerate lost body parts, such as entire limbs.

Publication: 'Dopamine Controls Neurogenesis in the Adult Salamander Midbrain in Homeostasis and during Regeneration of Dopamine Neurons', Anders A Berg, Matthew Kirkham, Heng Wang, Jonas Frisén & Andras Simon, Cell Stem Cell, online 7 April 2011.

Source:
Karolinska Institutet

 

New Technique Allows Noninvasive Tracking Of Stem Cells In The Brain

A new technique using "quantum dots" produced through nanotechnology is a promising approach to monitoring the effects of stem cell therapies for stroke and other types of brain damage, reports the April issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

The researchers report the successful use of "near-infrared fluorescence labeling" to track the behavior of injected stem cells in brain-injured rats. "The results open up new opportunities to develop non-invasive near-infrared fluorescence imaging...to track bone marrow stem cells transplanted into the human brain," write Dr. Taku Sugiyama and colleagues of Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Quantum Dots Allow Monitoring of Stem Cell Therapy for Brain Injury

The researchers used bone marrow stem cells to treat induced brain injuries, similar to stroke, in rats. Before injection, the stem cells were labeled with "quantum dots" a biocompatible, fluorescent semiconductor created using nanotechnology.

Other fluorescence techniques used to label stem cells have an important limitation their relatively short wavelengths don't easily penetrate through bone and skin. The quantum dots emit near-infrared light, with much longer wavelengths that can easily penetrate tissues. This allowed the researchers to monitor the behavior of stem cells within the brain after transplantation using a computer-assisted 3-D imaging system.

Using this technology, Dr. Sugiyama and colleagues were able to detect near-infrared fluorescence from the stem cells as they moved to and incorporated themselves into the area around the injured area of the brain. Reflecting the stem cells' behavior, the fluorescence increased gradually, peaking at four weeks after injection.

The fluorescence remained detectable for up to eight weeks. The findings were confirmed by direct examination of the brains.

Stem cell transplantation is a potentially valuable treatment for stroke and other central nervous system disorders. The use of stem cells developed from the patient's own bone marrow is a particularly promising approach. For example, a study in the March issue of Neurosurgery reported that bone marrow stem cell transplantation was a "logistically feasible and safe" approach to treatment of severe traumatic brain injury in children.

However, some type of imaging system is needed to monitor the activity of stem cells as they travel to the injured area and develop into new brain cells. "Such techniques would be crucial to validate the therapeutic benefits of bone marrow stem cell transplantation for central nervous system disorders," Dr. Sugiyama and coauthors write.

Near-infrared fluorescence labeling using quantum dots appears to provide a noninvasive technique for monitoring the effects of stem cell transplantation in the rat brain. Further research will be needed to see if similar techniques can be developed and used in humans. If so, this technology would be an important part of experimental stem cell therapies to promote functional recovery of the brain after stroke or other types of injury.

Source: Lippincott Williams & Wilkins