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What can stem cells teach us about bipolar disorder?

By Kara Gavin


First stem cell study of bipolar disorder yields promising results, U-M and Prechter Fund scientists say.

These cells, made from the skin of people with bipolar disorder, may help scientists understand the condition and develop new treatments. (Image courtesy of UMHS.)

These cells, made from the skin of people with bipolar disorder, may help scientists understand the condition and develop new treatments. (Image courtesy of UMHS.)

What makes a person bipolar, prone to manic highs and deep, depressed lows? Why does bipolar disorder run so strongly in families, even though no single gene is to blame? And why is it so hard to find new treatments for a condition that affects 200 million people worldwide?

New stem cell research published by scientists from the University of Michigan Medical School, and fueled by the Heinz C. Prechter Bipolar Research Fund, may help scientists find answers to these questions.

The team used skin from people with bipolar disorder to derive the first-ever stem cell lines specific to the condition. In a new paper inTranslational Psychiatrythey report how they transformed the stem cells into neurons, similar to those found in the brain – and compared them to cells derived from people without bipolar disorder.

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

It’s the first time scientists have directly measured differences in brain cell formation and function between people with bipolar disorder and those without.

The researchers are from the Medical School’s Department of Cell & Developmental Biology and Department of Psychiatry, and U-M’s Depression Center

Stem cells as a window on bipolar disorder

The team used a type of stem cell called induced pluripotent stem cells, or iPSCs. By taking small samples of skin cells and exposing them to carefully controlled conditions, the team coaxed them to turn into stem cells that held the potential to become any type of cell. With further coaxing, the cells became neurons.

“This gives us a model that we can use to examine how cells behave as they develop into neurons,”  says Sue O’Shea, PhD, the U-M stem cell specialist who co-led the work. “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.”

A small skin sample from a person with bipolar disorder can yield stem cells that can be coaxed to become neurons just like those in the brain. (Image courtesy of UMHS.)

A small skin sample from a person with bipolar disorder can yield stem cells that can be coaxed to become neurons just like those in the brain. (Image courtesy of UMHS.)

“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, MD, principal investigator of the Prechter Bipolar Research Fund and its programs.

“For instance,” he continues, “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.”

The research was supported by donations from the Heinz C. Prechter Bipolar Research Fund, the Steven M. Schwartzberg Memorial Fund, and the Joshua Judson Stern Foundation. The A. Alfred Taubman Medical Research Institute at the U-M Medical School also supported the work, which was reviewed and approved by the U-M Human Pluripotent Stem Cell Research Oversight Committee and Institutional Review Board.

Read more stories about medical advances at U-M.
O’Shea, a professor in the Department of Cell & Developmental Biology and director of the U-M Pluripotent Stem Cell Research Lab, and McInnis, the Upjohn Woodworth Professor of Bipolar Disorder and Depression in the Department of Psychiatry, are co-senior authors of the new paper.

McInnis, who sees firsthand the impact that bipolar disorder has on patients and the frustration they and their families feel about the lack of treatment options, says the new research could take treatment of bipolar disorder into the era of personalized medicine.

Not only could stem cell research help find new treatments, it may also lead to a way to target treatment to each patient based on their specific profile – and avoid the trial-and-error approach to treatment that leaves many patients with uncontrolled symptoms.

More about the findings

The skin samples were used to derive 42 iPSC lines. When the team measured gene expression first in the stem cells, and then re-evaluated the cells once they had become neurons, very specific differences emerged between the cells derived from bipolar disorder patients and those without the condition.

These neurons - derived from stem cells made from the skin of people with bipolar disorder - communicated with one another differently than neurons made from the skin of people without bipolar disorder. (Image courtesy of UMHS.)

These neurons – derived from stem cells made from the skin of people with bipolar disorder – communicated with one another differently than neurons made from the skin of people without bipolar disorder. (Image courtesy of UMHS.)

Specifically, the bipolar neurons expressed more genes for membrane receptors and ion channels than non-bipolar cells, particularly those receptors and channels involved in the sending and receiving of calcium signals between cells.

Calcium signals are already known to be crucial to neuron development and function. So, the new findings support the idea that genetic differences expressed early during brain development may have a lot to do with the development of bipolar disorder symptoms – and other mental health conditions that arise later in life, especially in the teen and young adult years.

Meanwhile, the cells’ signaling patterns changed in different ways when the researchers introduced lithium, which many bipolar patients take to regulate their moods, but which causes side effects. In general, lithium alters the way 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.

Like misdirected letters and packages at the post office, the neurons made from bipolar disorder patients also differed in how they were “addressed” during development for delivery to certain areas of the brain. This may have an impact on brain development, too.

The researchers also found differences in microRNA expression in bipolar cells – tiny fragments of RNA that play key roles in the “reading” of genes. This supports the emerging concept that bipolar disorder arises from a combination of genetic vulnerabilities.

The researchers are already developing stem cell lines from other trial participants with bipolar disorder, though it takes months to derive each line and obtain mature neurons that can be studied. They will share their cell lines with other researchers via the Prechter Repository at U-M. They also hope to develop a way to use the cells to screen drugs rapidly, called an assay.

Haiming Chen, MD, and Cindy DeLong, PhD, manager of the pluripotent stem cell core laboratory, are co-first authors of the paper.

Reference: Translational Psychiatry, early online publication, March 25, 2014.

This story comes courtesy of the University of Michigan Health System, which first published it March 25, 2014.

Kara Gavin

Kara Gavin

KARA GAVIN is a science/medical writer, media relations officer and communications adviser in the public relations and marketing communications department of the U-M Health System. She stepped back into this role in March 2012 after several years as PR director. Gavin also a founding member, executive committee member, and French horn player with the U-M Life Sciences Orchestra. Follow her on Twitter: @karag.


  • Cheryl Williams Blake - 1971

    I am teaching an Intro to Psychology class and we are just beginning to study Bi-polar disorder. This very timely research will bring about some great discussions for class.


    • Jan Larkey - Husband: 1975

      Cheryl, I do hope the new definitions of bipolar disorder include unipolar mania. My mother, diagnosed at age 66, died at age 92, having had only 1 depression and about 60 manic episodes. My book Rocket Momma, to be published in the spring of 2014, reveals what life is like within the family when a parent is ill. Books written by a child of a bipolar parent are rare. It is written in my child, teen and adult voices to reveal the impact this disease has on a child through the years.


  • Julie Hatfield - 1962

    Any research you can do on this horrible disease, which my youngest son has, will be welcomed. My son inherited the gene from his father and I was not told about the family illness until after I married him. The suffering I have watched should not happen to any human being.


  • Tim Sujek - 1967

    This article implies that the stem cell lines created are from adult stem cells, rather than embryonic stem cells. I have heard of several different advances from research on adult stem cells, but have not heard of any success of embryonic stem cell research. If this research is truly using adult stem cells, then it would be good to inform the reader of what kind of cells are really being used.


  • Harriette Dorkin - 1958

    I have a step grandson who has been diagnosed as bipolar. Has been trying for 4 plus years to get disability. Cannot work. Some drugs work very well, but the hassle to find a Dr and an insurance company to take care of him because he has no money is terrible. We suspect that his mom may be bipolar. It showed up in his early 20′s. He is 26 now. Hopefully your research will bring results in his lifetime.


    • Ken Lawler - 1977

      See my posted comment about the disability claim. It can be done, but it isn’t easy. You’ll need strong medical support.


  • Ken Lawler - 1977

    A close family relative has bipolar disorder, and has made her life a mess for years. At long last, in January, she received a disability award from the Social Security Administration after a 2-decade history of attempting to work and always being let go. So at least she will have some financial means now.

    On the other hand, it has taken many years of working with psychiatrists to find the right mix of medication to at least control the symptoms. It would be wonderful if this research could yield a personalized approach that could recommend the right medicines at the start. Many patients would benefit.


  • CAROLYN POISSANT - 1981, 1987

    People also need to be educated about the MANY facets and versions fo bi-polar disorder. I was treated for “major degression” my entire life, including after having a nervous breakdown, and I was put on a slew of anti-depressants, which only made things worse. I have always held fairly stressful professional jobs, but having a very low threshold for emotional response is extremely difficult to contain. Our society expects perfection in the workplace, which is virtually impossible for even a “high functioning” person with bi-polar disorder. Patience is key.


  • Jan Larkey - husband: Patrick Larkey PhD 1975

    I’m elated to read about your research and the possible benefits for not only the patient with bipolar disorder, but also their families.I have written Rocket Momma, my forthcoming memoir about the impact my bipolar mother’s behavior had on me, her daughter. Finally diagnosed as bipolar-manic when she was 66, lithium did stabilize her–when she would take it.
    To have a way to make a correct diagnosis and to have personalized medication would have made such a difference in our lives. My hope is that my book–and your research–will help other daughters and sons cope with the impact of having a bipolar parent.