neurons from induced pluripotent stem cells
March 26, 2014

Bipolar Disorder Stem Cell Study Opens Doors To Potential New Treatments

[ Watch the Video: First Stem Cell Study of Bipolar Disorder Yields Promising Results ]

April Flowers for - Your Universe Online

Bipolar disorder affects 200 million people globally, and yet there are so many questions surrounding the condition. Why are individuals with bipolar disorder prone to manic highs and deep, depressed lows? If there is no single gene to blame, why does bipolar disorder run so strongly in families? And why, with the enormous number of people suffering from bipolar disorder, is it so hard to find new treatments?

A new study from the University of Michigan Medical School, funded by the Heinz C. Prechter Bipolar Research Fund, reveals that the answers might actually be found within our stem cells.

To derive the first-ever stem cell lines specific to bipolar disorder, the research team used skin from individuals who suffer from the condition. They transformed these cells into neurons, similar to those found in the brain, then compared them to cells derived from people without the disorder.

Very specific differences in how these neurons behave and communicate with each other were revealed by the comparison, which also identified striking differences in how the neurons respond to lithium, the most common treatment for bipolar disorder.

This study represents the first time researchers have directly measured differences in brain cell formation and function between individuals with and without bipolar disorder.

The type of stem cells used for this study are called induced pluripotent stem cells (iPSCs). The team coaxed the sample cells to turn into stem cells that held the potential to become any type of cell by exposing the small samples of skin cells to carefully controlled conditions. Further coaxing turned the iPSCs into neurons.

"This gives us a model that we can use to examine how cells behave as they develop into neurons. Already, we see that cells from people with bipolar disorder are different in how often they express certain genes, how they differentiate into neurons, how they communicate, and how they respond to lithium," says Sue O'Shea, Ph.D., an experienced U-M stem cell specialist.

"We're very excited about these findings. But we're only just beginning to understand what we can do with these cells to help answer the many unanswered questions in bipolar disorder's origins and treatment," says Melvin McInnis, M.D., principal investigator of the Prechter Bipolar Research Fund and its programs.

"For instance, we can now envision being able to test new drug candidates in these cells, to screen possible medications proactively instead of having to discover them fortuitously."

McInnis works directly with bipolar patients and their families, seeing firsthand the impact the condition has on them. He said the new research could take treatment of bipolar disorder into the era of more personalized medicine. Stem cell research could help find new treatment options, as well as lead to a way to create targeted treatments for each patient—based on their specific profile. It might also help to avoid the trial and error approach to treatment used currently that leaves many patients with uncontrolled symptoms.

Forty-two iPSC lines were derived from the skin samples. The team first measured gene expression in the stem cells, then again once the cells had become neurons. They found that very specific differences emerged between the cells derived from bipolar disorder patients and those without the condition.

The team found that the bipolar neurons expressed more genes for membrane receptors and ion channels than the non-bipolar cells—specifically, those receptors and channels involved in the sending and receiving of calcium signals between cells.

Scientists already know that calcium signals are crucial to neuron development and function. The findings of this new study support the theory that genetic differences expressed early during brain development may have a lot to do with the development of bipolar disorder symptoms, as well as other mental health conditions that emerge later in life, specifically in the teen and young adult years.

When the researchers introduced lithium, the cells' signaling patterns changed in different ways. These changed signaling patterns allow many bipolar patients to regulate their moods, but the lithium causes side effects that can be disabling. Lithium works by altering the way the calcium signals are sent and received—and the new cell lines will make it possible to study this effect specifically in bipolar disorder-specific cells.

The bipolar neurons differed in how they were "addressed" during development for delivery to certain areas of the brain, much like misdirected letters at the post office, which might also have an effect on brain development.

Another key finding of the study is differences in microRNA expression in bipolar cells. MicroRNA are tiny fragments of RNA that play key roles in the "reading" of genes, which supports the rising theory that bipolar disorder arises from a combination of genetic vulnerabilities.

Although it takes months to derive each line and obtain mature neurons that can be studied, the team is continuing their research by developing stem cell lines from other trial participants with bipolar disorder. They plan to share their cell lines with other research studies via the Prechter Repository at U-M, as well as developing a way to use the cells to screen drugs rapidly, called an assay.

The findings of this study were reported in a recent issue of Translational Psychiatry.